Liver transplantation: review of the literature. Part 3: Medical complications

The first attempted human orthotopic liver transplantation, in 1963, involved a child with biliary atresia, who died on the operating table as a result of uncontrollable coagulopathy. Improvements in immunosuppression, surgical technique, medical imaging and postoperative care, as well as more stringent patient selection, have allowed the development of liver transplantation and its universal acceptance as the treatment for a variety of liver diseases. The radiologist plays a major role in the multidisciplinary transplantation team and must be familiar with each stage of orthotopic liver transplantation and its associated complications. In the first article of this series (Can Assoc Radiol J 1997;48[3]: 171-178), the authors reviewed the anatomic features and current concepts relevant to orthotopic liver transplantation. In the second article (Can Assoc Radiol J 1997;48[4]: 231-242), they discussed the vascular and biliary complications of the operation. This, the third and final article in the series, covers the medical complications.     

Percutaneous transhepatic endoscopic electrohydraulic lithotripsy of biliary tract calculi after orthotopic liver transplantation

The development of biliary tract calculi after orthotopic liver transplantation presents a unique clinical problem. Previously described techniques for removing biliary stones by shock wave lithotripsy, litholytic therapy with oral bile acids, and endoscopic mechanical extraction may be ineffective or contraindicated in liver transplant patients. For this reason, percutaneous transhepatic electrohydraulic lithotripsy (EHL) was performed using an 11 French flexible ureteroscope in two pediatric patients who developed biliary tract calculi following orthotopic liver transplant. There were no complications and postoperative follow-up over 4 years has been uneventful. To our knowledge, these represent the first reported cases of percutaneous transhepatic endoscopic EHL to fragment biliary tract stones in a transplanted liver, which for us has been a safe and effective therapeutic option.     

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.     

Infection complicating percutaneous liver biopsy in liver transplant recipients

There is controversy about the frequency of and risk factors for infectious complications of percutaneous liver biopsy in liver transplant recipients. The aim of this study was to identify the incidence and nature of complications associated with liver biopsy after orthotopic liver transplantation (OLT), with particular emphasis on infection. The medical records of all patients undergoing OLT between January 1990 and August 1994 were reviewed retrospectively to identify complications requiring hospitalization within one week of percutaneous liver biopsy. The nature and severity of complications were recorded and possible risk factors for infectious complications were examined. One hundred ninety-eight patients underwent 1,136 percutaneous liver biopsies. There were eleven complications (0.96%), including as follows: 7 infections, 3 bleeding episodes, and 1 vasovagal reaction. Infections after percutaneous liver biopsy included fever and bacteremia (n = 6), and fever without bacteremia (n = 1). All infections developed only in patients with underlying biliary tract abnormalities; the frequency of infection was higher (9.8%) in patients with choledochojejunostomy when compared with those with choledochocholedochostomy (1.4%). Bacteremia was more likely caused by skin flora in patients with choledochocholedochostomy (CDC) and by enteric bacteria in patients with choledochojejunostomy (CDJ). All infections were treated successfully with parenteral antibiotics. We conclude that biliary tract abnormalities are the primary risk factors for infection after percutaneous liver biopsy, although the risk is higher in patients with CDJ than with CDC. These data support the use of antibiotic prophylaxis before percutaneous liver biopsy in OLT recipients with biliary tract abnormalities.     

Paediatric liver transplantation: a 10 year experience in Taiwan

Between March 1984 and August 1994, 13 orthotopic liver transplantations were performed in 13 patients < or = 25 years of age. The indications included Wilson's disease (n = 7), biliary atresia (n = 4), choledochal cyst (n = 1) and hepatitis C cirrhosis (n = 1). Technical variants included full-size (n = 11), reduced-size (n = 1) and living-related (n = 1) liver transplantation. These recent technical innovations have offered an expanded donor pool for earlier transplantation, shorter waiting times and excellent quality grafts. Surgical complications occurred in six patients; all required additional surgery. Biliary complications were encountered more commonly in our earlier patients. Our actuarial patient and graft survival rate is 92% at 2 years. The long-term follow-up of our liver-transplanted Wilson's disease patients provides confirmatory evidence that orthotopic liver transplantation cures the underlying metabolic defect with complete normalization of biochemical abnormalities of copper metabolism, reversal of neurological impairments and the disappearance of Kayser-Fleischer corneal rings. The high rate of patient survival and excellent rehabilitation indicate that with prudent clinical judgement, liver transplantation can be achieved with an acceptable rate of morbidity, mortality and cost in a setting where manpower and donor organs are very limited.     

Hibernating myocardium: a hypometabolic state for energy conservation

Because of the anatomical features associated with situs inversus, technical difficulties will be encountered during orthotopic liver transplantation. This report describes the case of a patient with situs inversus totalis and end-stage liver disease from biliary atresia who was treated by segmental orthotopic liver transplantation. The segmental graft was safely placed in the left subphrenic space, and a suitable orientation was obtained for anastomoses of the hilar vessels. Chronic rejection necessitated retransplantation, by the same method, 19 months later. This technique has potential advantages in coping with anatomical obstacles encountered in patients with situs inversus.     

Traumatic neuroma with biliary duct obstruction after orthotopic liver transplantation

BACKGROUND: Traumatic neuromas may develop after injury to nerve fibers encased in Schwann cells. The incidence of symptomatic neural tumors appears to be low after orthotopic liver transplantation (OLT). Only two cases of biliary stricture caused by infiltrating traumatic neuroma have been described previously. METHODS: We report two new cases of biliary tract obstruction after OLT that failed to respond to percutaneous balloon dilatation and were corrected by a resection of the bile duct stricture followed by biliary reconstruction with a Roux-en-Y jejunal loop. RESULTS: The first patient (17 months after OLT) had a traumatic neuroma appearing as a distinct mass with nerve bundles confirmed histologically; the traumatic neuroma in the second patient (5 months after OLT) was a nerve stump with infiltration of nervous elements in the bile duct. Both patients recovered without complications. CONCLUSIONS: Traumatic neuromas should be considered in the differential diagnosis of late biliary stricture after OLT, in particular when not responding to percutaneous dilatation or stenting.     

Medical informatics in perinatology project AGUSTINA in Argentina

Biliary atresia, a progressive obliterative process involving the bile ducts, has its onset in the newborn period. It is characterized by worsening cholestasis, hepatic fibrosis, and cirrhosis, which lead to portal hypertension and a decline in hepatic synthetic function. Untreated, the outcome is uniformly fatal. The two major milestones toward improved treatment of this disease have been the Kasai portoenterostomy and orthotopic liver transplantation. There has been discussion regarding transplantation as primary therapy, but portoenterostomy remains the standard of care as first-line intervention. Hepatic transplantation, done more frequently for biliary atresia than for any other cause of liver failure in the pediatric population, offers improved survival and quality of life to those for whom the Kasai operation fails. The etiology of biliary atresia remains poorly understood. Working toward a better understanding of this disease, recent investigations target more precise characterization of the hepatic pathology and seek to identify possible causative agents and predictors of favorable outcome. Recent advances in the understanding of biliary atresia published between December 1995 and November 1996 are the focus of this review.     

Liver transplantation in Europe for patients with acute liver failure

Approximately 11% of all liver transplants performed in Europe are for acute liver failure, with one-year patient survival rates ranging between 50% and 75%. This review summarizes the selection, perioperative management, and outcome of patients transplanted for acute liver failure, with particular reference to the experience at the H?pital Paul Brousse in Paris and at King's College Hospital, London. In both centers, the decision to proceed to liver transplantation is based on criteria that predict a survival of less than 20% with medical management alone. Infectious complications and cerebral edema remain the most common causes of death, and highlight the importance of intensive monitoring and early treatment of perioperative complications. In selected patients, auxiliary partial orthotopic liver transplantation may be a therapeutic option, with the potential for native liver generation and eventual immunosuppression withdrawal in approximately two-thirds of patients.     

The current epizootic situation of prospects for eradicating rabies

Between January 1995 and December 1997 42 liver transplantations were performed in Centre for cardiovascular surgery and transplantation's in Brno. The patients were divided into two groups. The first group consist of 27 transplantations, where the biliary reconstruction was performed by means of choledochocholedochostomy or choledochojejunostomy over a drain. The drain was used on the first 20 patients for initial irrigation and for the decompression of the biliary tree later on. It was used only for the decompression in the last 7 patients of this group. The second group consist of 14 patients, where the choledochocholedochostomy was performed without any drain. The rate of the biliary complications was significantly higher in the first group. Nine biliary obstructions, 6 leaks a and 6 cholangitis occurred. Four patients died in consequence of the biliary complications. There was no biliary complication in the second group. Choledochocholedochostomy without a drain is considered as a method of choice for biliary tract reconstruction in liver transplantation.     

Role of surgical therapy in the treatment of refractory ascites

In 5-10% of cases ascites is not controlled by medical therapy and is defined refractory. These patients may be submitted to one of the four following surgical options: portal-systemic shunt, peritoneo-venous shunt, transjugular intrahepatic portal-systemic shunt, orthotopic liver transplantation. Although the portal-systemic shunt is efficient in clearing ascites, it does not improve the survival, which depends on liver function, and it is complicated by an important incidence of encephalopathy. Since the patients with refractory ascites and good hepatic risk are not usually many, it is possible to understand why derivative surgery has been disappointing with this indication. Although the peritoneo-venous shunt is associated with a significant rate of valve obstruction, it is an easy, effective and not expensive treatment. So, till now, it has been considered the first choice procedure of refractory ascites, if any situations, determinating the onset of postoperative complications, are not present. Recently a new method has been introduced in the therapy of portal hypertension, the transjugular intrahepatic portal-systemic shunt. This is a bloodless portal-systemic derivation and so it has caused great enthusiasm even if the available data are insufficient to give a definitive opinion on its role in management of ascites. Certainly the liver transplantation, which presents the great advantage to treat both the cirrhosis and its complications, seems to be the most rational therapy for these patients. However, at least for this moment, the well-known absence of organ donors makes still actual the palliative surgical measures.     

Partial hepatic resection for ischemic graft damage after liver transplantation: a graft-saving option?

BACKGROUND: Intrahepatic biliary strictures or parenchymal infarcts may occur after liver transplantation as a complication of ischemic damage to the graft. In some selected cases the lesions appear to be confined to a part of the liver. We report our experience with partial graft resection in this setting. METHODS: From January 1984 to December 1991, 286 liver transplantations were performed in 257 recipients. Seven patients, three children and four adults, underwent partial hepatectomy 3 to 218 weeks after liver transplantation of a full-size graft. The clinical presentation included septic parenchymal infarcts (n = 4) and nonanastomotic biliary strictures (n = 3) complicating (n = 5) artery thrombosis or not (n = 2). There were four left hepatectomies, two left lobectomies, and one right hepatectomy. In four instances partial hepatectomy was performed after failed attempt at biliary reconstruction (n = 2) or arterial revascularization (n = 2). Partial graft resection was performed extrafascially without Pringle's maneuver and mobilization of the remnant liver to preserve its vascularization. RESULTS: No surgical complications occurred, and none of the patients experienced acute hepatic failure during the postoperative period. All patients were discharged home 10 to 96 days (median, 23 days) after liver resection. Two patients had recurrent ischemic cholangitis. One patient underwent successful regrafting for recurrent Budd-Chiari syndrome; one patient died of tumor recurrence. Six patients were alive with a follow-up ranging from 12 to 45 months. CONCLUSIONS: These results suggest that partial graft resection is a safe and graft-saving option after liver transplantation in selected patients with localized ischemic damage of the graft.     

Transplantation of islets of Langerhans in patients with insulin-requiring diabetes mellitus undergoing orthotopic liver transplantation--the Miami experience

Most patients with cirrhosis of the liver have detectable insulin resistance. In 60-80% of patients with cirrhosis, impaired glucose tolerance can be uncovered; approximately 20% of these patients eventually develop overt diabetes. Theoretically, insulin resistance and glucose intolerance could be improved or reversed by orthotopic liver transplantation alone or in association with a simultaneous transplant of pancreatic islet cells from the same donor. To investigate these possibilities we initiated a pilot study of simultaneous liver and pancreatic islet cell transplantation in seven patients with diabetes and liver cirrhosis. Donor bone marrow cells were also infused to enhance the acceptance of the grafts. Seven patients who received only orthotopic liver transplantation and donor bone marrow cells were used as historical controls. The preliminary results of this pilot trial suggest that islet cell transplantation in conjunction with orthotopic liver transplantation improves glucose metabolism in patients with liver cirrhosis in association with reduced insulin requirements and HbA1c levels. These results were evident in spite of pre- and post-transplant basal C-peptide levels that were unchanged. Further evaluation of the effects of orthotopic liver transplantation with or without islet cell transplantation will require a randomized prospective trial including accurate metabolic evaluation with the euglycemic insulin clamp technique.     

Systemic lupus erythematosus: description of a pediatric series

OBJECTIVE: To analyze possible causative mechanisms for intracranial hemorrhage after orthotopic liver transplantation. DESIGN: We conducted a retrospective survey of medical records and a case-control comparison in patients who had undergone liver transplantation during the period 1986 through 1992. MATERIAL AND METHODS: In a group of 8 patients with intracranial hemorrhage after orthotopic liver transplantation and a control series of 207 patients who had undergone liver transplantation but did not have intracranial hemorrhage, we summarized pertinent clinical and laboratory data and statistically analyzed potential risk factors for hemorrhage. RESULTS: In the eight study patients, intracerebral hematomas were located in the parietal or frontal lobe in six, the cerebellum in one, and the putamen in one. Autopsy demonstrated a Candida-associated mycotic aneurysm in one of the eight patients, and one had disseminated aspergillosis. No statistically significant differences in thrombocytopenia, hypertension, extracranial bleeding sites, or cyclosporine-related neurotoxicity were found when these patients were compared with the control series. Bacteremia or fungemia was found in five of the eight patients with intracerebral hemorrhages (62%) but in only 11% of the control group (P = 0.03; Fisher's exact test). CONCLUSION: Overwhelming infections, thrombocytopenia, or both may have a role in intracerebral hemorrhage after liver transplantation.     

Orthotopic transplantation of a partial hepatic autograft in dogs

The purpose of this study was to investigate the availability of an orthotopic transplantation of partial hepatic autograft in dogs as a means of surgical training. Male mongrel dogs weighting 10-15 kg were used. The left lobe of the liver was harvested while preserving the left branches of the portal vein, hepatic artery and bile duct, and the left hepatic vein. The remnant liver was removed while preserving the inferior vena cava using a veno-venous bypass. Orthotopic transplantation of the autograft was performed while anastomosing the left hepatic vein to the inferior vena cava, portal and arterial reconstruction, and external biliary drainage. Thirteen out of 29 dogs survived more than 48 h after transplantation. However, 6 out of 13 dogs were sacrificed after developing bile peritonitis due to a dislodgement of the biliary catheter, and only two dogs were able to survive for 7 days after transplantation. The arterial ketone body ratio recovered to 1.0 within 1 h after reperfusion, and the ratio of the dogs that survived for more than 48 h remained above 1.0 until sacrifice. Orthotopic transplantation of a partial hepatic autograft is a useful and simple procedure to train surgeons for partial liver transplantation.     

Biliary stenosis in patients treated with liver transplantation. Diagnostic approach

Between April 1986 and August 1994, 393 orthotopic liver transplantation (OLT) have been performed at "12 de Octubre" Hospital. Among these ones we consider 274 OLT made in 223 adults and in 47 children (4 intraoperative deaths). The reconstruction of the biliary tract was performed with a choledocho-choledochostomy with T tube (CD-CD T) in 131 patients, a choledocho-choledochostomy without T tube or stent (CD-CD) in 75, a Roux-en-y-hepatico-jejunostomy (H-J) in 248, a hepatico-jejunostomy with stent (H-J St) in 13 and a choledocho-cholecisto-jejunostomy (CD-CC-J) in 3 patients. Thirthy six (13.3%) patients developed biliary complications (30 adults and 6 childrens). Fourteen (18.6%) occurred in CD-CD reconstruction and 13 (11.4%) in CD-CD T. The most common complications were leakage and stricture. Thirteen ERCP were performed in 12 patients (1 failed), all adults (CD-CD T: 3; CD-CD: 10). The main indication for ERCP was cholestasis and inability of non invasive methods ultrasound, scintigraphy and computerized tomography in determining the underlying etiology. ERCP was successful in all 12 patients: detecting strictures in 8, strictures + lithiasis in 1, stricture+lekage in 1 and leakage in 2. No complications were encountered after ERCP in our patients. ERCP is the method of choice in diagnosis of biliary complications in CD-CD biliary reconstruction.     

Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy

BACKGROUND: In transplantation, novel methods are required to augment the supply of donor organs. We report the first domino liver transplant in which a patient with familial amyloid polyneuropathy (FAP) received an orthotopic split liver graft, and her explanted liver was donated to another patient. Three successful liver transplants were thus achieved from the one cadaver liver. PATIENTS AND METHODS: A cadaveric donor liver was split and the left lobe was grafted into a child with biliary atresia. The right lobe was transplanted into a woman with FAP associated with the transthyretin Met30 variant. Her own otherwise healthy liver was donated to a patient with cirrhosis and hepatocellular carcinoma. RESULTS: Fifteen months after transplantation, all three recipients are well with normal liver function. The domino recipient developed inferior vena cava stricturing at the level of anastomosis after surgery with resultant ascites, requiring dilatation and LeVeen shunt insertion. Serum amyloid P component scintigraphy showed amyloid regression in the domino donor and to date has not identified any amyloid deposits in the recipient, who also remains free of tumor recurrence. CONCLUSIONS: Domino transplantation using the livers from patients with FAP may be justified for patients whose disease condition precludes a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation rather than long-term cure is the aim.     

Reduction of voltage-dependent currents by ethanol contributes to inhibition of NMDA receptor-mediated excitatory synaptic transmission

BACKGROUND/AIMS: Primary graft dysfunction is difficult to predict. We have previously shown that indocyanine green clearance measured at 24 h following orthotopic liver transplantation predicts graft survival and outcome. We prospectively evaluated the use of indocyanine green clearance (with a cut-off value of 200 ml/min) as a marker of graft function following orthotopic liver transplantation and investigated its relationship with the markers of reperfusion injury during orthotopic liver transplantation. METHODS: In all patients indocyanine green clearance was measured at 24 h. Repeated blood samples were taken before, during the anhepatic and reperfusion phase and up to 12 h following orthotopic liver transplantation to measure the levels of neutrophil elastase and reactive oxygen intermediates. All patients studied had normal hepatic arterial pulse on Doppler-ultrasound post orthotopic liver transplantation. RESULTS: All patients with indocyanine green clearance >200 ml/min recovered following orthotopic liver transplantation and remained well up to 3 months of follow up. Four patients had an indocyanine green clearance <200 ml/min; three were re-transplanted for graft failure within 3 days of the transplant, while one survived after prolonged intensive support and hospitalization. Indocyanine green clearance significantly correlated with reactive oxygen intermediates production and neutrophil elastase during orthotopic liver transplantation (r=-0.61, p<0.002 and r=-0.66, p<0.0009, respectively). Indocyanine green clearance was also significantly correlated with alanine aminotransferase and prothrombin time at 24 h post-transplantation (r=-0.35, p<0.02 and r=-0.4, p<0.0077, respectively). CONCLUSION: Indocyanine green reflects the degree of reperfusion injury and is a good early marker of primary graft function. Indocyanine green clearance over 200 ml/min is associated with favorable outcome.     

Low level of interleukin 10 synthesis during liver allograft rejection

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.     

Clinical denouement and mutation analysis of patients with cystic fibrosis undergoing liver transplantation for biliary cirrhosis

OBJECTIVE: To describe the clinical characteristics of patients with cystic fibrosis considered for liver transplantation and the clinical outcome after transplantation. METHODS: Patient charts were reviewed. Mutation analysis was performed on blood or liver tissue samples with a panel of 17 mutations. RESULTS: Eight patients (five girls) with cystic fibrosis have undergone orthotopic liver transplantation for biliary cirrhosis. Mean age at transplantation was 12.0 years +/- 7.7 years (range, 9 months to 23 years). Preoperatively, seven patients had mild to moderate pulmonary dysfunction and one moderate to severe pulmonary dysfunction. All patients required pancreatic enzyme replacement, and four patients required insulin for diabetes mellitus. The 1-year survival rate was 75%, with no deaths related to septic events. Mean time of follow-up the six operative survivors was 4.1 years +/- 1.9 years. Pulmonary function testing, in those serially tested, showed that forced expiratory volume in 1 second was maintained or improved and that forced vital capacity improved after transplantation. Mutation analysis showed the following genotypes: four patients, delta F508/delta F508; one patient, delta F508/N1303K; and three patients, delta F508/unknown. CONCLUSIONS: Despite the high risk of transplantation, these encouraging results indicate that liver transplantation should be considered for patients with cystic fibrosis and complications of end-stage liver disease. We could not demonstrate an unusual pattern of CF gene mutations in these patients with severe liver disease. It appeared that immunosuppressive agents did not have a deleterious effect on pulmonary function.