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Liver transplantation 

Liver transplantation
Chapter:
Liver transplantation
Author(s):

Gideon M. Hirschfield

, Michael E.D. Allison

, and Graeme J.M. Alexander

DOI:
10.1093/med/9780199204854.003.152205_update_001

August 28, 2014: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Source of livers for transplantation—non-heart-beating donors are increasingly used, albeit with increased complication rates; living related liver donation is now widespread and routine in many centres.

Updated on 28 November 2012. The previous version of this content can be found here.
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Essentials

Liver transplantation is considered for patients with liver disease that is predicted to shorten life or causes symptoms that preclude an acceptable quality of life and for individuals with life-shortening genetic disease that can be cured by transplantation. One-year survival exceeds 90%, 5-year survival approaches 80%, and individual median survivals exceed 20 years.

The selection of patients and timing of transplantation is difficult, since both premature transplantation and delayed grafting can shorten life. Manifestations of chronic liver disease that should prompt referral to a transplant centre include hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, jaundice, malnutrition, hepatic osteodystrophy, hepatorenal syndrome, reversed portal vein blood flow, portal vein thrombosis, and hepatocellular carcinoma. Super-urgent liver transplantation is often life saving for those with acute liver failure (encephalopathy, coagulopathy, liver disease of <6 months duration).

Liver transplantation usually involves a whole liver graft from a deceased donor, but innovations include the use of split livers, auxiliary grafts, living related transplantation, and more recently the use of non-heart-beating donors. Size matching between donor and recipient is important, but transplantation across the ABO barrier is performed in exceptional circumstances. HLA matching and pre-existing donor sensitization are not considered important. Therapeutic immunosuppression is most commonly with triple therapy: calcineurin inhibitor (tacrolimus, ciclosporin), azathioprine, and prednisolone.

In the immediate postoperative period most complications relate to the anastamoses, bleeding or poor graft function. Early postoperative complications include infection (bacterial, viral (cytomegalovirus), fungal), problems with vascular and biliary anastomoses, and acute rejection. In the longer term the consequences of immune suppression (impaired renal function, increased cardiovascular risk, infection and malignancy) remain important, alongside chronic vascular rejection and disease recurrence.

Introduction

Liver transplantation is an established procedure with 90% 1-year survival, 5-year survival approaching 80% and individual median survival exceeding 20 years. Improvements in quality of life are such that a return to normal personal, professional and family life is expected. The current challenge is to ensure equity of access in the context of an increasingly limited donor pool.

Indications for liver transplantation

Liver transplantation is considered for patients with liver disease that is predicted to shorten life, less often for subjects in whom symptoms of liver disease preclude an acceptable quality of life and individuals in whom life shortening genetic disease can be cured by transplantation. The most common indications are shown in Box 15.22.5.1.

Assessment and waiting for transplantation

The selection of patients and timing of transplantation is difficult, since both premature transplantation and delayed grafting can shorten life. Organ transplantation should occur when there is clear evidence of benefit; a composite assessment of medical, surgical, and psychological factors that may preclude transplantation is essential. All individuals who may benefit from liver transplantation should be referred for early assessment. Manifestations of chronic liver disease prompting referral include hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, jaundice, malnutrition, hepatic osteodystrophy, hepatorenal syndrome, reversed portal vein blood flow, portal vein thrombosis, and hepatocellular carcinoma.

The concept of minimum listing criteria for liver transplantation has become an accepted component of the assessment process to ensure equity of access to, and maximal benefit from, an increasingly limited donor pool. Increasing age, renal dysfunction, poor nutritional status, and jaundice are associated with reduced survival after transplantation. Liver disease severity algorithms such as MELD (bilirubin, creatinine, INR) and UKELD (bilirubin, creatinine, INR, and Na+) are used routinely as a basis for listing as well as for prioritization and removal from the waiting list. Patients with diseases in which a synthesis-based algorithm would put them at a disadvantage (e.g. hepatocellular carcinoma) need to be managed in a modified way.

The basis for many presumed contraindications is the likelihood that 5-year survival will fall beneath 50% as a result of operative risk, pre-existing medical conditions, or both. Extrahepatic and metastatic malignancy is still considered a contraindication with rare exceptions (certain neuroendocrine tumours and haemangioendothelioma). Many other factors may contribute to a decision not to proceed, including continued injecting drug or substance abuse, severe cardiorespiratory disease (hepatopulmonary syndrome or portopulmonary hypertension are anaesthetic risk factors but not necessarily contraindications), malnutrition, and (increasingly) obesity. Surgical factors such as portal vein thrombosis and previous laparotomy need to be considered individually. Factors such as age, HIV coinfection, previous ischaemic heart disease, diabetes, and severe psychiatric illness are not per se contraindications to transplantation.

Individuals who are turned down should be re-assessed if circumstances change, and offered the opportunity of a second opinion.

Listed patients need close management. Vaccination against hepatitis A virus is pragmatic and againstt hepatitis B virus (HBV) is recommended for naïve, as donor organs positive for anti-HBc carry a risk of subsequent HBV infection. Factors that may require temporary or permanent suspension from the list include sepsis, hyponatraemia (risk of central pontine myelinolysis), renal impairment, new portal vein thrombosis, new or further growth of hepatocellular carcinoma, and substance/alcohol abuse.

Specific disorders

Acute and subacute liver failure

Super urgent liver transplantation is often life saving for those with acute liver failure (encephalopathy, coagulopathy, liver disease of <6 months duration). The chance of spontaneous recovery is least in those with subacute liver failure, whose clinical course may mimic chronic liver disease. Various criteria based on outcome allow selection of patients with acute liver failure for transplantation. Most use a combination of aetiology, age, coagulopathy, renal failure, acidosis, and bilirubin to identify those with poor survival without transplantation at 1 year. When compared to patients with chronic liver failure the 1-year survival is lower, but these patients are often cured by transplantation and many are young; the longer-term outcome is excellent. Psychiatric follow-up may be indicated in a minority.

Chronic liver disease

Alcohol

The outcome of transplantation for alcohol-related liver disease is equivalent to that following transplantation for other chronic liver disorders. Abstinence is an absolute requirement because clinical status may improve substantially such that patients may not need transplantation. Most units look for a 6- to 12-month alcohol-free period, with a clear commitment to lifelong abstinence because patients may improve with abstinence. Factors that predict recidivism include alcohol consumption in the year prior to transplantation, the duration of abstinence, and the extent of social support. Historically, severe acute alcoholic hepatitis was not an accepted indication for transplantation because of continued alcohol consumption at presentation and poor post-transplant survival, but this is under review currently.

Chronic viral hepatitis

Chronic infection with hepatitis B, C, or D are all indications for transplantation if patients have complications. Results improve if viraemia is controlled or eradicated pretransplant.

Hepatobiliary malignancy

Surgery, where possible, is the best treatment for hepatocellular carcinoma (HCC). Choosing between resection and transplantation is a difficult decision. In patients with a normal background liver or in those with compensated cirrhosis, resection may be possible. In others with more advanced liver disease transplantation is beneficial with a low risk of recurrence if tumour bulk is limited. According to the Milan criteria transplantation is indicated if there is a single tumour of less than 5 cm diameter or three tumours all less than 3 cm in size, in the absence of portal vein involvement or extrahepatic spread. Imaging modalities include ultrasound, contrast CT, MRI, and hepatic angiography.

The fibrolamellar variant of HCC is more common in young patients without cirrhosis and is slower growing, and resection is performed more commonly than transplantation. Outside clinical trials, transplantation cannot be recommended for cholangiocarcinoma because of unacceptable recurrence rates. Very occasionally transplantation has a role in the management of neuroendocrine tumours (particularly if the primary can be resected), hepatic haemangioendothelioma and large biliary cystadenoma.

Non-alcohol-related steatohepatitis

As a component of the metabolic syndrome, non-alcohol-related steatohepatitis leads to chronic liver disease, cirrhosis, and HCC. Fibrosis progression may be ameliorated by aggressive management of modifiable risk factors but, as an indication for transplantation, this disease is increasingly important. Patients need careful assessment of their cardiovascular risk profile pre-transplant and continued careful management of diabetes, hyperlipidaemia, hypertension, and weight is needed post-transplant. Disease recurrence is common.

Primary biliary cirrhosis

Most patients with primary biliary cirrhosis (PBC) do not need liver transplantation, and most clinicians accept that ursodeoxycholic acid at appropriate doses has improved transplant free survival. However those with decompensated liver disease, HCC, or severe unremitting symptoms benefit from transplantation. A bilirubin in excess of 100 µmol/litre predicts a high mortality without transplantation in the absence of other indications.

Primary sclerosing cholangitis

The timing of transplantation for primary sclerosing cholangitis (PSC) is difficult. The disease has a fluctuating course; previous bowel surgery increases the perioperative risk, and patients face a 10 to 20% lifetime risk of inoperable cholangiocarcinoma. Transplantation is not indicated as prophylaxis against malignancy. Frequent episodes of jaundice (often unremitting) or cholangitis should prompt assessment. Endoscopic retrograde cholangiopancreatography (ERCP) (with biliary cytology) and endoscopic ultrasonography may help the assessment of a superimposed cholangiocarcinoma; CA19-9, a tumour marker associated with cholangiocarcinoma, is not wholly reliable (marked elevations are seen with biliary disease and sepsis). Careful surveillance and management of inflammatory bowel disease are essential. Patients without a colon at transplant may fare better in the long term.

Autoimmune hepatitis

Transplantation can be avoided in many patients with autoimmune hepatitis, even in those who present with chronic liver failure. Transplants are performed for those with complications of endstage liver disease and, less often, poor control despite appropriate therapy.

Budd–Chiari syndrome

The presentation of hepatic vein thrombosis can be acute or chronic. In those with acute liver failure, transplantation is accepted first-line therapy. In those with a less dramatic presentation, radiological intervention (hepatic vein angioplasty and/or transjugular intrahepatic portosystemic shunting) or surgical shunts can be effective, followed by long-term anticoagulation. Transplantation remains an option. The majority of patients with Budd–Chiari syndrome have an underlying coagulopathy; appropriate investigation (e.g. thrombophilia screen and Jak-2 mutation analysis) and treatment of underlying haematological disease is essential. Most patients require anticoagulation from the early postoperative period.

Metabolic/genetic disease

Transplantation is successful where metabolic/genetic disorders lead to liver failure. These include Wilson’s disease, α‎1-antitrypsin deficiency (increasingly recognized as an important cofactor in many chronic liver diseases), Gaucher’s disease, glycogen storage disease, Crigler–Najar syndrome, and familial intrahepatic cholestasis syndromes. Patients with haemochromatosis may avoid transplantation with early diagnosis and venesection, but may present with complications of chronic liver disease, including HCC. This group has an increased post-transplant morbidity related to cardiovascular disease, diabetes and an increased susceptibility to postoperative bacterial infection.

Polycystic liver disease, unlike polycystic kidney disease, causes hepatic failure rarely, but patients may suffer pain and abdominal distension such that transplantation is considered. Those with associated renal failure may benefit from combined liver–kidney transplantation. Hereditary haemorrhagic telangiectasia may be associated with massive hepatic haemangioma that leads to portal hypertension, secondary biliary disease (ischaemic bile duct injury due to shunting), or HCC; in these rare cases transplantation may be indicated.

Patients with cystic fibrosis (CF) may develop a secondary biliary cirrhosis and significant portal hypertension in addition to cardiorespiratory disease. Empirically it appears that ursodeoxycholic acid slows down the progression of CF-associated liver disease; occasional well-selected patients benefit from transplantation. Nutritional gains from transplantation may aid longer-term cardiorespiratory function. Realistically, because of donor organ shortages, most centres offer multi-visceral transplantation rarely.

Surgical gene therapy

This term describes the practice of liver transplantation to treat life-threatening inherited disorders in which the genetic abnormality is cured by giving the recipient a healthy donor liver. Examples include primary oxalosis (unless performed in childhood, concurrent renal transplantation is usually performed), hypercholesterolaemia, and familial amyloidosis. Unique features of individual diseases require modifications to standard transplant management, e.g. risk of heart block in transthyretin amyloidosis and risk of acute oxalate nephropathy following liver–kidney transplantation in oxalosis.

Transplant procedure

Liver transplantation usually involves a whole liver graft from a deceased donor, but innovations continue in the use of split livers, auxiliary grafts, and living related transplantation. Early morbidity and mortality continue to improve with increased surgical and anaesthetic expertise; massive transfusion is rare.

Donor organ

Liver transplantationExtended criteria have been introduced to widen the pool of donors because of increasing disparity between the number of available organs and possible recipients, albeit with the potential for greater recipient morbidity and mortality. Livers may now be used with mild or moderate steatosis, from individuals with previous exposure to HBV, from individuals with HCV, from donors over the age of 65 and from non-heart-beating donors. Extrahepatic malignancy in the donor is assessed on an individual basis. Non-heart-beating donors are increasingly, used, albeit with increased complication rates. Living related liver donation is now widespread and routine in many centres.

Size matching between donor and recipient is important. Transplantation across the ABO barrier is performed rarely, but it is routine to match for blood group, except in acute liver failure. HLA matching and pre-existing donor sensitization appear less important than with other solid organ transplants. The intention is to implant the new liver so that the cold ischaemic time is less than 12 h. In situ perfusion with cold University of Wisconsin solution has permitted prolongation of the cold ischaemic time.

Surgical aspects

The transplantation procedure consists of three operations. Hepatectomy, which can be difficult with portal hypertension or previous abdominal surgery, is followed by the anhepatic phase with liver implantation. Reperfusion and abdominal closure follow. Variations in techniques exist for caval anastomosis. In up to 20% of patients the donor hepatic arteries have anomalous anatomy requiring adjustments to the nature of the hepatic artery anastomosis. Veno-venous bypass with extracorporeal circulation of blood via the portal vein back into the systemic circulation is used on occasion and reduces subsequent rates of renal failure and sepsis. The biliary anastomosis can be carried out as duct-to-duct or as duct-to-small bowel (Roux-en-Y-hepatico-jejunostomy). Primary Roux loop formation is carried out where there are doubts about the vascular supply to the biliary tree, with re-transplantation, and often in patients with PSC, who have a risk of cholangiocarcinoma in residual recipient biliary tissue. Previous techniques using the gallbladder as a biliary conduit were less successful and the use of an externally draining T-tube over a duct-to-duct anastomosis has lost favour. Donor cholecystectomy removes the potential for a denervated, atonic gallbladder to act as a nidus for stone formation and sepsis.

Recent innovations in transplantation have focused on using split liver grafts, in which the donor liver is divided and offered to two recipients. This carries greater procedural risk but utilizes donor organs more effectively. Auxiliary transplantation, where the recipient liver remains in place and another whole or partial (reduced size) liver is transplanted adjacently, may have a role in acute liver failure and the treatment of genetic liver disease. Problems with the vascular anastomosis and the lack of a reliable method of proportionally dividing the portal vein blood flow between two livers causes significant morbidity. Living related transplantation is now well established. The advantages are those of an elective procedure with excellent donor liver function, minimal cold/warm ischaemia, and lower rates of rejection. There are increased vascular and biliary complication rates for the recipient, along with the potential for ‘small-for-size syndrome’. The donor operation has a defined morbidity and mortality.

Anaesthetic aspects

Close attention to donor haemodynamics are important to avoid organ injury during retrieval. During the transplant itself the anaesthetist has the task of maintaining adequate cardiorespiratory function, in the face of significant swings in cardiac output, cardiac filling, and systemic vascular resistance. Particularly critical moments can occur on mobilization of the recipient liver, on manipulation of the inferior vena cava, and during the anhepatic and reperfusion phases. Bleeding complications have been reduced by the use of aprotinin and by monitoring coagulation closely, e.g. thromboelastography.

Post-transplant course

Surgical, medical, and immunological factors account for morbidity and mortality. In the immediate postoperative period most complications relate to bleeding or poor graft function. Early postoperative complications include sepsis, problems with vascular and biliary anastomosis, and acute rejection. In the late postoperative period the consequences of immune suppression (renal function, cardiovascular risk, infections, and malignancy) are more important, alongside chronic vascular rejection and disease recurrence.

Immediate

Bleeding varies from inconsequential to life threatening, with the associated complications of haemodynamic instability and massive transfusion. Very early graft failure is suggested by coma following withdrawal of sedation, a rapidly rising prothrombin time, acidosis, high lactatem high insulin requirements, thrombocytopenia, and hyperkalaemia. The differential diagnosis is primary non-function, non-thrombotic graft infarction, or hepatic artery thrombosis. The patient develops acute liver (and multiorgan) failure and imaging by ultrasound and/or angiography of the graft vascular supply is important. Super-urgent retransplantation is life saving. The blood supply to the liver can also be affected catastrophically by inappropriate use of inotropes, and marginal graft function can be made critical by inappropriate vasoconstriction. Hyperacute rejection (antibody mediated) is extremely rare; thus a positive cross-match is not a contraindication.

Early

The combination of a demanding procedure in immunocompromised, chronically ill individuals can make diagnosis of complications challenging, with a low specificity for routine symptoms and signs. In addition to blood tests, investigations such as ultrasonography, CT, MRI, and liver biopsy are often sufficient for diagnosis, although more invasive investigations (e.g. ERCP, angiography, exploratory surgery) are sometimes needed.

Sepsis

All patients are at risk of sepsis, but those transplanted for acute liver failure and/or with renal failure face additional risk. The sites of infection are commonly chest, urine, blood, abdomen (wound, haematomas, bilomas) and indwelling cannulae, although other locations of sepsis to consider include frontal sinuses, teeth, and heart valves. The risk of sepsis is increased with a second transplant.

Most units give 48 h of antibiotic prophylaxis; the choice is dependent on local microbiology advice, methicillin-resistant Staphylococcus aureus (MRSA) status, and antimicrobial allergy. Subsequent courses of antibiotics should be guided by culture.

Cytomegalovirus (CMV) can cause disease in the first month or so post-transplant. The advent of valganciclovir (an oral prodrug of ganciclovir) has simplified prophylaxis, which is indicated if the donor has serological evidence of past CMV, but the recipient is negative. Clinical disease with CMV is diminished by 3 months prophylaxis; if disease occurs after completing prophylaxis it is usually less severe. Primary or secondary CMV viraemia can be identified early by surveillance with PCR of plasma for CMV DNA. Active disease (cytopenia, pneumonitis, colitis, hepatitis, retinitis, wound infection) can be treated by reduced immune suppression and with intravenous ganciclovir; oral valganciclovir may be less effective in this setting. Reduced immune suppression alone may be sufficient in secondary reactivation. Herpes simplex is reactivated commonly in the first 2 weeks post-transplant; symptomatic infection is uncommon but warrants topical or systemic treatment with aciclovir. Varicella zoster infection, usually much later in the course, should always be treated. Occasionally marked hepatitis from donor-derived herpesviruses such as herpes simplex or Epstein–Barr virus (EBV) occurs and a low threshold for virological testing is needed to make the diagnosis. Infections with human herpesviruses 6 and 8 are now documented, but occur at a late stage.

Fungal infection can be devastating, especially if associated with vascular anastomoses. High-risk groups include individuals transplanted for acute liver failure, patients with renal failure, and individuals with ischaemic grafts. Prophylaxis with fluconazole is recommended and is effective against the commonly isolated candida species. Tacrolimus metabolism is modified by fluconazole. Most patients are discharged with topical prophylaxis in the form of nystatin or amphotericin lozenges. Systemic disease may require treatment with higher doses of fluconazole, or where appropriate amphotericin B or caspofungin, and should be guided by culture.

Lymphopenia is a risk factor for infection with Pneumocystis jirovecii but prophylaxis with co-trimoxazole (or dapsone if allergic) is usually effective. Toxoplasmosis is rare but prophylaxis is recommended if the donor is seropositive and the recipient naive.

Anastomotic complications

Each surgical anastomosis is subject to complications. Hepatic artery thrombosis (1–2% incidence except in paediatric practice) may be suspected by worsening liver function tests, zone 3 centrilobular ischaemia on liver biopsy, the biliary leak, or the development of nonanastomotic biliary strictures. Bacterial or fungal sepsis may be associated. Diagnosis usually requires ultrasonography or angiography (CT, MR, or classical) and management usually entails retransplantation. Patients transplanted for PSC are more prone to arterial thrombosis. Hepatic artery stenosis may be amenable to vascular reconstruction. Portal vein thrombosis or stenosis is less common and maybe suspected by the development of ascites. Caval anastomotic strictures are infrequent, but may present as rapid weight gain, recurrent pleural effusions, ascites, peripheral oedema, protein-losing enteropathy, or pulmonary emboli. Angioplasty with or without stenting can be successful. Biliary complications relate to either leaks or strictures. Anastomotic strictures are usually technical, whereas non-anastomotic strictures often relate to hepatic ischaemia, although recurrent PSC and Roux loop reflux cholangiopathy are in the differential. The use of non-heart-beating donors is particularly associated with nonanastomotic biliary complications. Treatment options include therapeutic ERCP, external biliary drainage, biliary reconstruction, and retransplantation.

Acute rejection and graft-vs-host disease

Acute cellular rejection of the graft is common and probably occurs to some degree in most subjects. The target tissues include bile ducts and endothelial cells (hepatic artery, portal, and central veins). Symptoms are nonspecific, including fever, jaundice, and pain. More often acute rejection is suspected on the basis of deterioration in liver function, especially the bilirubin accompanied by eosinophilia; rejection needing treatment is less likely if the patient is not jaundiced, but liver biopsy confirmation is recommended in order to grade the severity of rejection. Pulsed doses of methylprednisolone are prescribed for moderate or severe rejection. Steroid-resistant rejection (which can be treated with lymphocyte depletion) and multiple episodes of acute rejection, although uncommon, carry a poor prognosis for the longer term.

Very rarely donor-derived lymphocytes generate graft-vs-host disease (GVHD). The patient (often underweight and previously alcoholic with lymphopenia) presents within a few months with systemic disease manifest as rash, diarrhoea, and pancytopenia. In contrast to classical GVHD seen in bone marrow transplantation, the liver is ‘immune’ to attack and liver function tests are classically normal. The diagnosis of acute GVHD can be difficult, since many of its features are similar to drug reactions or viral infection; the demonstration by molecular testing for donor lymphoid chimaerism is diagnostic. Outcome is almost universally fatal, with progressive malnutrition and intractable sepsis. No treatment modality is proven.

Late

Although late presentations of technical complications do occur, such as delayed hepatic artery thrombosis, intrahepatic biliary strictures, and recurrent cholangitis, these are less important than medical complications.

Renal failure and cardiovascular disease

In the past it was estimated that by 5 years post-transplant 10 to 20% of patients would develop chronic renal failure, usually related to calcineurin inhibitor toxicity but also secondary to diabetes and vascular disease. The day 30 creatinine is a good predictor of long-term renal function. The risk is lower now with careful calcineurin dosing in the early postoperative period, when patients often have marginal renal function, and with use of alternative non-nephrotoxic immune suppression including sirolimus. Patients are also at heightened risk from hypertension, hypercholesterolaemia, obesity, metabolic syndrome, and diabetes. Ambulatory post-transplant care focuses on these issues to reduce the probability of cardiovascular events.

Malignancy

A spectrum of predominantly EBV-driven B-cell lymphomas occurs with an incidence of 2 to 4%. It is more common in paediatric practice, especially in naive recipients. Although disease in or around the liver is most common, widespread disease is not infrequent. Management is focused on minimizing (or even stopping) immunosuppression, along with systemic chemo- and biological therapies such as rituximab with CHOP. The outcome was poor but has been much improved in the past decade. Disease resolution can be tempered by development of chronic rejection. There is a substantial increase in the incidence of almost all carcinomas, some relating to pre-transplant risk factors, others to the consequences of long-term immunosuppression. Sun protection, appropriate breast and cervical screening, and smoking cessation are recommended.

Osteodystrophy

Osteoporosis, and more rarely osteomalacia, are important but often overlooked complications of chronic liver disease and both conditions are associated with significant morbidity through fractures resulting in pain, deformity, and immobility. The increasing trend to rapidly wean steroids has reduced post-transplant fracture rates. Patients should have bone density measured, in addition to vitamin D and testosterone levels, and appropriate treatment initiated (e.g. calcium/vitamin D and bisphosphonates).

Chronic rejection

Chronic rejection is a vasculopathy with characteristic obliteration by foamy macrophages of the main branches of the hepatic artery and bile duct loss (‘vanishing bile ducts’) probably secondary to ischaemia. Chronic rejection is more common in those with severe acute rejection, steroid-resistant acute rejection, or multiple episodes of acute rejection. It can also occur after switching immunosuppression. Presentation can be acute, with an initial cellular component, or more insidious. The switch from ciclosporin to tacrolimus and the prevention and treatment of CMV disease has probably reduced its incidence. Re-transplantation may be needed, but carries a higher risk of chronic rejection in subsequent grafts.

Immune suppression

To achieve tolerance, which is an active immunological process between the transplant recipient and the graft, donor antigens must imprint their pattern of specificity on the recipient immune system. Ironically immunosuppressive agents, such as tacrolimus, while reducing rejection probably prevent true tolerance. Liver allografts have immunologic advantages over other organs and liver transplantation in patients appears to protect against rejection of other organs transplanted from the same donor. Currently used immunosuppressive drugs are outlined in Table 15.22.5.1.

Table 15.22.5.1 Currently used immunosuppressive agents

Drug

Mechanism

Side effects

Comments

Prednisolone

Synthetic corticosteroid with broad anti-inflammatory effects

Weight gain, hyperglycaemia, osteoporosis

Enhances HBV and HCV replication

Azathioprine

Purine synthesis inhibitor that inhibits cell proliferation

Marrow suppression, pancreatitis, veno-occlusive disease

Harmful interaction with allopurinol

Mycophenolate mofetil

Mycophenolic acid inhibits de novo purine synthesis by inhibiting inosine monophosphate dehydrogenase

Diarrhoea, marrow suppression

Tacrolimus

Calcineurin inhibitor: macrolide antibiotic that inhibits both T-lymphocyte signal transduction and IL-2 transcription

Nephrotoxicity, neurotoxicity, hypertension, diabetes

Reduces the rate of chronic rejection as compared to cyclosporin and more reliably absorbed

Cyclosporin

Calcineurin inhibitor: inhibition of T-lymphocyte signal transduction and IL-2 transcription

Nephrotoxicity, neurotoxicity, hypertension

Sirolimus

Inhibition of IL-2 receptor signalling (mTOR inhibitor)

Pneumonitis, atypical infection, impaired wound healing

Antitumour and antifibrotic effects may be of value in HCC and HCV

Antilymphocyte and antithymocyte globulin

Lymphocyte depletion

Infection, serum sickness, lymphoma

Retains a role in steroid-resistant acute rejection

Anti-CD25 monoclonal antibodies

IL-2 receptor blockade

Hypersensitivity reactions

May allow delayed tacrolimus use in those with renal impairment

A wider range of alternative immune suppressive agents has improved outcome and allowed protocols to be tailored to the aetiology of the original disease, the risk of disease recurrence and renal function. Most start with triple therapy: calcineurin inhibitor (tacrolimus is used more often than ciclosporin), azathioprine, and prednisolone. Corticosteroids (we favour 20 mg prednisolone daily) are weaned over 6 weeks, but azathioprine (approximately 1 mg/kg) is continued for 6 to 12 months.

Calcineurin inhibitors form the backbone of treatment but side effects are substantial, including hypertension, hyperlipidaemia, weight gain, nephrotoxicity, and neurotoxicity. Tacrolimus is diabetogenic; ciclosporin causes hirsutism and gum hypertrophy.

Different scenarios demand different approaches. Where there is concern about renal function some centres delay introduction of calcineurin inhibitors, using monoclonal antibodies against the interleukin-2 receptor instead (e.g. basiliximab). When calcineurin inhibitors cause renal toxicity, sirolimus is an effective alternative. Many centres favour mycophenolate mofetil rather than azathioprine as it is perceived to be more lymphocyte specific. Comparative data are lacking and cost is an important factor.

Antilymphocyte and antithymocyte globulin are often effective following failed treatment for acute rejection; there are concerns about sustained lymphopenia.

Recurrent disease

Disease ‘recurrence’ in the graft is a significant concern.

Hepatitis B (HBV)

Accelerated, devastating graft infection by HBV occurs in those transplanted for HBV (particularly if HBV DNA positive at transplant) or in recipients who receive a donor organ positive for anti-HBc when appropriate prophylaxis is not prescribed. Graft infection is prevented by the combination of pooled HBV immunoglobulin (HBIg) and combination antiviral chemotherapy. HBIg revolutionized treatment of this group of patients. With the dual use of antiviral agents the duration of prophylaxis with HBIg can be shortened. Prolonged antiviral mono-therapy with lamivudine has inevitably driven resistant strains and alternative antiviral agents such as adefovir, tenofovir, and entecavir, preferably in carefully chosen combinations, now prevent disease recurrence. Prednisolone enhances HBV replication in vivo and in vitro and early steroid withdrawal is recommended.

Hepatitis C (HCV)

Liver transplantation for HCV does not cure the disease and infection of the graft, with the potential for accelerated disease, is nearly inevitable. A significant proportion of patients have cirrhosis by 5 to 10 years and a small proportion lose the graft within 1 to 2 years. Factors associated with graft damage include the age and quality of the donor (older, more marginal livers are more prone to recurrence) and the cumulative dose of immune suppression. Many transplant units avoid using marginal donors in HCV-positive recipients where possible and some use a steroid-free regime. Rapamycin has in vitro antifibrogenic properties and trials are under way of its use in the context of HCV-related fibrosis post-transplant. Antiviral therapy post-transplant with pegylated interferon-α‎ in combination with ribavirin is effective in selected patients post-transplant, although historically this combination was regarded as ineffective with the risk of rejection. The role of protease inhibitors in this group is uncertain.

Autoimmune hepatitis

Autoimmune hepatitis can ‘recur’, causing graft damage and loss. Patients transplanted for autoimmune hepatitis appear to have an increased risk of acute rejection; many centres use long-term dual or triple immunosuppression. A smaller group of individuals, particularly those transplanted as children, develop de novo ‘alloimmune hepatitis’ which responds to enhanced immunosuppression. This may be a variant of rejection; mismatch between donor and recipient for expression of the enzyme glutathione S-transferase T1 is one recognized risk factor.

Primary sclerosing cholangitis (PSC)

PSC is likely to ‘recur’ in the graft of perhaps 20% of individuals within 5 years of transplantation and may cause graft dysfunction and cholangitis. Immune suppression does not prevent disease recurrence. Risk factors for recurrence include male sex and having an intact colon before transplantation. Despite immune suppression inflammatory bowel disease can be more severe after transplantation. Furthermore, colon cancer appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC. Annual colonoscopy in this population is therefore essential.

Primary biliary cirrhosis (PBC)

Recurrent PBC is well recognized and although cirrhosis with portal hypertension has been reported by 2 years, it is more commonly a histopathological diagnosis than a major clinical problem affecting graft function or patient survival. Interestingly there is a suggestion that ciclosporin (as opposed to tacrolimus) prolongs the median time to recurrence. There remains insufficient evidence to suggest adjusting immunosuppression regimes.

Alcohol

Recidivism for alcoholism and the development of alcohol-related liver disease after transplantation are well recognized. Approximately 20% of patients who undergo transplantation for alcoholic liver disease use alcohol post-transplant; one-third of these individuals exhibit repetitive or heavy drinking. Liver damage can lead to graft loss within 1 year if consumption is heavy.

The future of transplantation

Long-term survival following transplantation is a testament to the refinement of the entire procedure from assessment to post-transplant care. Future strategies must focus on avoiding transplantation. Surgical advances are needed to increase the donor pool, along with ongoing efforts to improve deceased donation rates. Safer, individualized, immune suppression will need major advances in the understanding and targeting of the immune system.

Further reading

Burroughs AK, et al. (2006). 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome. Lancet, 367, 225–32.Find this resource:

Muiesan P, Vergani D, Mieli-Vergani G (2007). Liver transplantation in children. J Hepatol, 46, 340–8.Find this resource:

Neuberger J (2004). Developments in liver transplantation. Gut, 53, 759–68.Find this resource:

O’Grady JG, et al. (2007). Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: poststudy surveillance to 3 years. Am J Transplant, 7, 137–41.Find this resource:

Wiesner R, et al. (2003). Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology, 124, 91–6.Find this resource: