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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Liver transplantation

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Department of Surgery, Charité, Humboldt University Berlin, Germany

The first human liver transplantation (LTx) was performed by T.E. Starzl in 1963. Improvements in surgical techniques, new immunosuppressants, the prolongation of the ischemic tolerance and the experience with indications and timing LTx has become an accepted clinical method in cases of end-stage liver diseases.

Based on United Network for Organ Sharing (UNOS) data on February 1998 the Kaplan-Meier 4 year survival rate after LTx in United States (28022 transplantations between October 1987 and December 1996) was 61.4% (std. err.: 0.3) for graft survival and 72.7 (std. err.: 0.3) for patient survival. Patient and graft survival rates depend on primary diagnosis (table I).

Table I. Patient and graft survival rates at three and five years, computed using the Kaplan-Meier method. (UNOS Scientific Registry data as of September 15, 1997) (10). “N” denotes the number of transplants from October 1987 through December 1995 for which a survival time could be determined, “n.c.” denotes not calculated for the unknown categories.

Table I

Patient and graft survival rates at three and five years, computed using the Kaplan-Meier method. (UNOS Scientific Registry data as of September 15, 1997) (10). “N” denotes the number of transplants from October 1987 through December 1995 (more...)

Definition, indications and contraindications for liver transplantation

In general there is an indication for LTx in all conventional incurable chronic and acute end-stage liver diseases (table II). Non-disease specific minimal listing criteria for LTx are a Child-Pugh score greater than 7 (class B or C) and portal hypertensive bleeding or a single episode of spontaneous bacterial peritonitis, irrespective of Child-Pugh-score. Hepatic malignancy, initially well accepted for LTx, should be an indication for transplantation in highly selected individuals. Absolute contraindications for LTx include life-threatening systemic diseases, uncontrolled extrahepatic bacterial or fungal infections, metastatic malignancy, active alcohol or drug abuse, and infections with human immunodificiency virus or active tuberculosis. Relative contraindications include portal vein thrombosis, ischemic cardiac disease, severe valvular heart disease, severe hypoxaemia resulting from right-to-left intrapulmonary shunts and non-compliance of the recipient for psychological, social or medical reasons.

Table II. Indications for liver transplantation (selection).

Table II

Indications for liver transplantation (selection).

The majority of LTx are performed orthotopically, heterotopic transplantations are assigned to cases like acute liver failure and metabolic diseases. The shortage of donor organs has lead to the development of techniques like transplantation of reduced-size organs (especially for small children), transplantation of “split-livers” (one donor organ is splitted ex-situ or in-situ into two transplantable liver lobes for two patients) and living-related LTx. Sequential orthotopic LTx (“Domino-liver-transplantation”) using the livers from patients with familial amyloid polyneuropathy undergoing LTx may be justified for patients whose condition preclude a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation is the aim.

Preoperative evaluation

The assessment of preoperative risk and the possibility of a preoperative improvement in the transplant recipient condition requires an interdisciplinary discussion between surgeons and other medical disciplines. Preoperative screening of the myocardial (stressEKG, echocardiography) and ventilatory function (chest X-ray, pulmonary function test, arterial blood gases), evaluation of renal function, coagulation status and endocrine changes are important. Pretransplantation workup includes serum-AST, serum-ALT, AP, gamma-GT, GLDH, bilirubine, serum-albumine, serum-proteine, ammonia, triglycerides, lipid-electrophoresis, blood glucose, serum iron, ferritin, electrolytes, blood urea nitrogen, creatinine, uric acid, urinalysis (sediment, proteine (24 h), creatinine-clearance (24 h)), blood count, differential white blood count and coagulation tests (prothrombine time, partial thromboplastin time, factors I, II, V, VII, X). A pretransplant evaluation for potential infectious diseases (serodiagnosis of hepatitis incl. HBV-DNA and HCV-RNA, tests for HIV, CMV, herpes simplex and zoster, EBV) and scanning for potential infectious foci (dental and otorhinolaryngology status) are important for the prevention and management of infectious complications in liver transplant recipients. Portal vein patency and situation of V. lienalis as well as V. mesenterica can be confirmed by doppler-ultrasound or helical CT scanning with intravenous contrast medium. CT scans are useful in determing the presence of tumors in cirrhosis and of liver volume. Angiography may be necessary for patients with abnormal portal vein findings, suspected cavernous transformation of the portal vein, and with porto-systemic shunts. Patients with primary sclerosing cholangitis have a greater risk of cholangiocellular carcinoma and should therefore undergo endoscopic retrograde cholangiopancretography (ERCP) or percutaneous transhepatic cholangiography (PTC) as well as brush-cytology in order to rule out this diagnosis.

Operative technique in liver transplantation

Removal of the recipient's native liver is a technically demanding step, particularly in the presence of portal hypertension associated with collateral circulation, coagulopathy and fragile liver tissue. Before hepatectomy portal vein and infrahepatic and suprahepatic inferior vena cava are occluded by clamps. In order to prevent congestion of visceral organs and hemodynamic disturbances a pump-driven veno-venous bypass system is applied rerouting blood flow from the infrahepatic V. cava and portal vein via V. axillaris into the suprahepatic venous system. Using the veno-venous bypass the incidence of postoperative renal insufficiency and generalized intestinal oedema is reduced and a volume-restrictive substitution therapy during preanheptic phase is possible. The native liver is then removed and the prepared donor organ is inserted. Anastomotic procedures start with end-to-end anastomosis of suprahepatic and infrahepatic inferior vena cava. Hepatic artery anastomosis will be performed corresponding to the anatomical situation. After decannulating the portal vein an end-to-end anastomosis will be performed. In order to prevent hyperkalemia through high potassium levels out of the preservation solution in the donor graft the liver is flushed with approximately 300–500 ml blood. Biliary anastomotic complications remain a major cause of morbidity in liver transplant recipients, ranging between 10% and 50% in large clinical series. Commonly performed techniques are end-to-end choledochocholedochostomy (CDCD) over a T-tube and choledochojejunostomy. Diseases of the extrahepatic biliary system are indications for choledochojejunostomy (i.e. biliary atresia, sclerosing cholangitis, cholangiocarcinoma). Both techniques are known to coincide with a relatively high incidence of leakage and stenosis of the bile duct anastomosis. Because of better perfusion in the anastomotic area and the possibility of creating an anastomosis up to a length of 10 to 12 mm side-to-side common bile duct anastomosis represents a safe technique of bile duct reconstruction and leads to a low technical complication rate.

A T-tube providing access for biliary imaging procedures and monitoring liver allograft function, can be utilized to control an early anastomotic leak and may prevent late anastomotic stricture. Stenting the bile duct over a T-tube is still discussed controversial. Although some authors conclude that routine use of a T-tube is unnecessary in most liver transplant patients, studies found a significantly lower incidence of biliary strictures and surgical revisions in patients with an end-to-end CDCD over T-tubes (1).

Liver transplantation with preservation of the recipient vena cava (the “piggy-back”-technique) has been proposed as an alternative to the traditional method. There are several advantages to this technique: retrocaval dissection or dissection of the right suprarenal compartment are not required, there is no problem of different sizes of recipient and donor vena cava and a veno-venous bypass system during anhepatic phase is unnecessary.

Postoperative management

Immunosuppressive therapy

There are significant variations in the regimens for immunosuppressive therapy used by different liver transplant centers. In general, most regimen include corticosteroids plus one calcineurin inhibitor such as cyclosporine A (Sandimmune® or Neoral®, CyA) or tacrolimus (Prograf®, FK506). Neoral is a microemulsion formulation of CyA, whose absorption is more uniform and less dependent on bile. Tacrolimus and cyclosporine A gain access to the cell cytoplasm by binding with isomerase proteins (Cyclophyllin for cyclosporine and FK-binding protein for tacrolimus), acting on the same enzyme system to prevent translocation of the signal evoked by an antigen stimulus, normally inducing the transcription of the intranuclear IL-2genes. The similarities extend to their side effects: both are nephrotoxic, neurotoxic and toxic to islets of Langerhans. When compared to cyclosporine on a dosage basis, tacrolimus appears to be 10 to 100 times more potent in its ability to inhibit IL-2. Large multicenter studies showed that with respect to 5-year patient and graft survival rates tacrolimus provides long-term immunosuppression comparable to that of cyclosporine, with trends toward increased survival rates with tacrolimus. The United States FK506 Study Group observed that the incidence of biopsy-confirmed acute rejection (68% versus 76% for CyA; p < 0.001) and corticosteroid-resistant rejection (19% versus 36% for CyA; p < 0.001) in the first year was significant lower in patients treated with tacrolimus compared with patients treated with cyclosporine. There were no other significant differences observed between both treatment groups in terms of types of rejection during subsequent years. Cumulative 5-year patient and graft survival rates were similar for the tacrolimus (79.0%, 71.8%) and cyclosporine groups (73.1%, 66.4%). However, patient halflife survival was longer for tacrolimus-treated patients (25.1 ± 5.1 years versus 15.2 ± 2.5 years; p = 0.049). 5-year patient survival rate was significantly higher with tacrolimus compared to cyclosporine among hepatitis C-positive patients. The incidence of malignancies, lymphoproliferative disorders, and late infections in tacrolimusbased regimen are similar to those observed with cyclosporine (2).

Due to improved and less variable bioavailibility of Neoral compared to Sandimmune early oral administration of Neoral is possible without routine intravenous CyA administration. According to the MILTON study the use of Neoral decreases the risk of acute rejection significantly, without increasing the risk of serious adverse events or renal dysfunction.

Initial dosage of tacrolimus is usually two daily doses (every 12 hours) of 0.05–0.1 mg/kg body weight, adjusted according to whole blood levels aiming at 5–15 ng/ml, depending on efficacy of preventing rejection and toxicity. The daily Neoral dose is adapted to cyclosporine levels and is adjusted to maintain trough whole blood concentrations between 150 and 350 ng/ml, starting after surgery as a oral dose of 5 to 7 5 mg/kg body weight. Additional immunosuppressive therapy usually consists of prednisolone starting with 1 mg/kg body weight daily, gradually tapered to a maintenance level of about 5–10 mg daily over the next several months.

Efforts are being made to develop more powerful immunosuppressive agents with more specific effects: a prospective randomized study comparing Neoral and tacrolimus with mycophenolate mofetil (CellCept®, MMF) demonstrated the feasibility of lowering the rejection incidence for both immunosuppressants (4). An open-label prospective randomized study with tacrolimus and steroids (double-drug therapy) versus tacrolimus, steroids, and MMF (triple-drug therapy) in primary adult liver transplant recipients showed similar patient and graft survival rates in both groups a trend to a lower incidence of rejection, reduced nephrotoxicity, and a lesser amount of maintenance corticosteroids in triple-drug therapy compared with double-drug therapy (5).

New immunosuppressive drugs have been introduced into clinical transplantation. Basiliximab (Simulect®) is a chimeric and daclizumab is a humanized IgG1 mouse/human monoclonal antibody. Both drugs bind to the alpha-chain of the IL-2 receptor. Recent trials showed that prophylaxis with 40 mg basiliximab in renal allograft recipients reduced the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns. First studies concerning liver transplant recipients are suggesting that therapy with basiliximab reduced acute rejection episodes, was safe, excellently tolerated and did not increase particularly the incidence of viral infections.

Early complications

Primary graft non-function occurs in 1–8% of cases and is a very serious complication. Comparable to acute liver failure with hepatorenal syndrome patients will show markedly abnormal liver function, minimal bile output, coagulopathy, oliguria and severe CNS changes. The terminal phase is characterized by coma, alkalosis, hyperkalemia, and hypoglycemia. Therapy for this condition is urgent retransplantation. In cases of severe toxic liver syndrome hepatectomy hours prior to retransplantation may be indicated.

Bleeding occurs more often in cases of graft dysfunction and hypothermia. In these cases substitution of coagulation factors and warming of the patient may be indicated. In cases of hyperfibrinolysis therapy with proteinase-inhibitors should be started. A persisted requirement for blood transfusions necessitates relaparatomy.

Persistent jaundice, increasing bilirubine, alkaline phosphatase and gamma glutamyltranspeptidase, fever, leucocytosis, drainage of bile via intraperitoneal drains and intraabdominal bile collection in ultrasound or CT-studies are suggesting a biliary leakage. The above mentioned clinical signs without bile in drainage fluid, may indicate bilary stenosis. Cholangiography - preferably via T-tube - and ultrasonography should be performed. Relaparatomy performing a choledochojejunostomy or endoscopic retrograde stent implantation may be indicated. Biliary leaks caused by hepatic artery thrombosis usually require retransplantation if establishing arterial perfusion by thrombectomy is unsuccessful.

Hepatic arterial thrombosis should be presumed in all graft-recipients with sudden high fever, elevation of liver enzymes and positive blood culture for Klebsiella, Pseudomonas, E. coli or enterococci, biliary leaks, or fulminant liver failure. For diagnosis a Doppler ultrasound and - if unsatisfactory hemodynamics are identified - arteriography should be performed. Reconstructive surgery or dilatation may be successful in early detected vascular complications - Doppler ultrasound for the detection of clinically unsuspected vascular complications should be performed routinely on a daily basis during the early postoperative phase. Retransplantation will be necessary in cases of acute hepatic gangrene and fulminant liver failure.

Portal vein thrombosis is often caused by technical failure; rejection or initial poor graft function are promoting thrombosis. Clinical signs are sudden increase of transaminases, ascites, severe encephalopathy, renal dysfunction and gastrointestinal bleeding. If a portal vein thrombosis is detected early thrombectomy may be possible — portal vein thrombosis during the early postoperative phase may lead to acute graft failure necessitating retransplantation.

Acute rejection episodes occur with an incidence of 20–40%. Clinical signs suggesting rejection are fever, reduced bile volume and pigment, swelling of graft, increased serum bilirubine and aminotransferase levels and decrease of levels of coagulation factors II and V. If acute rejection is suspected liver biopsy (Menghini needle biopsy) should be performed. Histologic features of acute rejection include portal infiltration, bile duct injury and endothelial inflammation. As soon as transplant rejection is confirmed, treatment with a steroid bolus (e.g. 500 mg intravenous methylprednisolone) for three consecutive days should be started. If no decrease of liver enzyme levels is detectable — biopsy should be performed. OKT3 is a monoclonal antibody used as T-cell-specific immunosuppressant in the treatment of steroid-resistant rejection, defined as failure to respond to steroid bolus therapy. The immunosuppressive effect is related to the elimination and modulation of T-cells after the binding of OKT3 and the specific antigen CD3+. In cases of steroid-resistant rejection in patients receiving primarily cyclosporine A-based immunosuppression early tacrolimus rescue therapy is the treatment of choice because of higher success rates and lower incidence of infectious, neurologic and renal complications compared to OKT3-therapy.

Infectious complications remain among the most significant causes of morbidity and mortality in patients undergoing liver transplantation. The incidence of cytomegalie (CMV) infection and disease in liver transplant recipients ranges from 23% to 100% and from 18% to 70% respectively. Clinical signs are usually mild, consisting of viremia, fever, leukopenia, thrombocytopenia, atypical lymphocytosis and malaise. In more serious cases, patients may develop hepatitis and pneumonitis. Although aciclovir is established for prophylaxis, many centers now use ganciclovir which has greater in vitro activity against CMV. In a randomized multicenter study prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous ganciclovir followed by high-dosage oral aciclovir is more effective than high-dosage oral aciclovir alone at reducing CMV infection and disease, even for CMV-negative recipients of CMV-positive grafts. The Oral Ganciclovir International Transplantation Study Group revealed in randomized multicenter placebo-controlled trial that oral ganciclovir is a safe and effective method for the prevention of CMV disease after orthotopic liver transplantation (6).

Epstein-Barr virus (EBV) infection in transplant recipients can lead to lymphomas termed posttransplantation lymphoproliferative disorders (PTLD) in 3% to 10% of solid organ transplant recipients with a resultant mortality of up to 70%. Most PTLD are malignancies of B lymphocytes and are linked to EBV infection, but the rare T lymphocyte PTLD have been inconsistently linked to EBV infection. Several treatments are currently used but multicenter studies are needed with regard to therapeutic strategy. Protocols utilizing preemptive intravenous ganciclovir in high-risk recipients (i.e., donor (D)+, recipient (R)-), combined with serial monitoring of peripheral blood for EBV by polymerase chain reaction (PCR) have decreased the overall incidence of PTLD from 10% to 5% in children receiving primary tacrolimus therapy after LTx (7).

Trimetohoprim-sulfamethoxacole is used in transplant recipients in an effort to prevent Pneumocystis carinii pneumonias, Nystatin is used to prevent and treat oropharyngeal candidiasis.

Late complications

In adults, 15% to 40% of liver transplant recipients have elevated serum cholesterol levels, and approximately 40% have hypertriglyceridemia. Obesity is a common though poorly studied problem in liver transplant recipients. Longterm immunosuppression with corticosteroids, CyA and tacrolimus results in a new onset of postoperative diabetes in 10% to 15% of liver transplant recipients. With improved survival of liver transplant recipients, chronic renal failure has become an important cause of morbidity.

Most liver diseases for which LTx is performed may recur. 8.7% PBC recurrence has been identified in a large series of patients with a long-term follow up, without affecting patient survival rate. Patients undergoing LTx for autoimmune hepatitis have an excellent survival rate although severe primary disease may recur. A large retrospective multicenter study revealed that the estimated risk of recurrence of autoimmune hepatitis in the graft increased over time: 8% over the first year and 68% five years after transplantation. Patient and graft survival do not appear to have decreased.

In a large European series, approximately 75% of patients who received transplants for HBV-cirrhosis without antiviral therapy had recurrence of hepatitis B in the allograft at a mean of 3.2 (± 2.7) months. The effective mainstay of prophylaxis is passive immunotherapy with hepatitis B immune globulin (HBIg). There are two major published trials using high-dose intravenous HBIg: The HBIg University of Virginia Protocol: HBIg 10,000 IU i.v. anhepatic, then 10,000 IU i.v. daily for the next 6 days. Subsequent doses of 10,000 IU are administered to keep antiHBs titers over 500 IU/ml. The University of California San Francisco uses a high-dose HBIg-protocol with HBIg 10,000 IU i.v. anhepatic, then daily for 7 days, then monthly thereafter. Both protocols led to a recurrence rate of less than 20% in all patients treated. Most European centers are aiming anti-HBs titers over 100 IU/ml. Antiviral therapy with lamivudine given at a dose of 100 mg/die for 12 weeks has proven effective in suppressing HBV replication, but long-term treatment will most likely be required in the majority of patients: the majority had recurrence of HBV-DNA after discontinuation of treatment. After recurrence, reduction of immunosuppression and a combination antiviral therapy should be considered. The current antiviral agents available for recurrent HBV are lamivudine and famciclovir (8).

Approximately 90% to 95% of patients with cirrhosis secondary to chronic hepatitis C before LTx develop recurrence with detectable HCV-RNA in serum, leading to recurrent graft hepatitis in more than 50%. De novo hepatitis C was reported to occur in 5% to 35% of patients who underwent LTx. Due to the fact that hepatitis C after LTx progresses to fibrosis and cirrhosis in only a minority of patients, that no decline in patient or graft survival can be demonstrated with up to 10 years of follow-up, and the lack of proven effective treatment for HCV, it is difficult to support a concept that all patients with recurrent disease should be treated at the present time. For treatment of chronic hepatitis C in nonimmunosuppressed patients a combination of interferon-a and ribavirin is effective. Only a single published study has shown control of viral replication and improvement in histological status when a combination regimen of ribavirin, and interferon-a is used in liver transplant recipients with recurrent hepatitis C. These results must be confirmed with randomized, controlled studies (9).

Ischemic type biliary lesions (ITBL) are defined as non-ischemic and non-immunological destruction of the graft's biliary tree after liver transplantation and are characterized by bile duct necroses leading to alterations of the ductal lumen, biliary leakage, stone or cast formation and, thereby, to cholestasis. ITBL of the extrahepatic as well as of the intrahepatic ducts may be treated by endoscopic procedures, including papillotomy, dilatation, extraction of stones or sludge, placement of nasobiliary tubes, or insertion of stents. In cases of impossible endoscopic treatment or ineffective interventions reconstructive surgery or retransplantation will be necessary.

Comment

Liver transplantation has matured from an experimental procedure reserved for desperately ill patients to an accepted, lifesaving operation. Nevertheless, numerous aspects of concerning indication for LTx, surgical techniques, of treatments infectious complications and especially the optimal immunosuppressive regimen are still under investigation and differ widely between transplant centers. There is a lack of large prospective randomized trials concerning treatment and possible prevention of recurrent hepatitis B and C and immunosuppressive regimens with newly developed immunosuppressive agents.

References

1.
Rabkin J M, Orloff S L, Reed M H, Wheeler L J, Corless C L, Benner K G, Flora K D, Rosen H R, Olyaei A J. Biliary tract complications of side-to-side without T tube versus end-to-end with or without T tube choledochocholedochostomy in liver transplant recipients. Transplantation. (1998);65(2):193–199. [PubMed: 9458013]
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Wiesner R H. A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation — A report of the United States FK506 study group. Transplantation. (1998);66:493–499. [PubMed: 9734494]
3.
Otto M G, Mayer A D, Clavien P A, Cavallari A, Gunawardena K A, Mueller E A. Randomized trial of cyclosporine microemulsion (neoral) versus conventional cyclosporine in liver transplantation: MILTON study. Multicentre International Study in Liver Transplantation of Neoral. Transplantation. (1998);66(12):1632–1640. [PubMed: 9884251]
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Fisher R A, Ham J M, Marcos A, Shiffman M L, Luketic V A, Kimball P M, Sanyal A J, Wolfe L, Chodorov A, Posner M P. A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation. (1998);66(12):1616–1621. [PubMed: 9884248]
5.
Jain A B, Hamad I, Rakela J, Dodson F, Kramer D, Demetris J, McMichael J, Starzl T E, Fung J J. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report. Transplantation. (1998);66(10):1395– 1398. [PMC free article: PMC2952474] [PubMed: 9846530]
6.
Gane E, Saliba F, Valdecasas G J, O'Grady J, Pescovitz M D, Lyman S, Robinson C A. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group. Lancet. (1997);350(9093):1729–1733. [PubMed: 9413463]
7.
McDiarmid S V, Jordan S, Lee G S, Toyoda M, Goss J A, Vargas J H, Martin M G, Bahar R, Maxfield A L, Ament M E, Busuttil R W. Prevention and preemptive therapy of posttransplant lymphoproliferative disease in pediatric liver recipients. Transplantation. (1998);66(12):1604–1611. [PubMed: 9884246]
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Dickson R C. Management of posttransplantation viral hepatitis — hepatitis B. Liver Transplantation and Surgery. (1998);5 (suppl 1):S73–S78. [PubMed: 9742497]
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Shiffman M L. Management of posttransplantation viral hepatitis C. Liver Transplantation and Surgery. (1998);5 (suppl 1):S79–S86. [PubMed: 9742498]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
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