Since the first successful liver transplant (LT), performed by Thomas Starzl in 1967 (Fricker, 2017), LT has become an accepted and effective treatment for a select cohort of patients with end-stage chronic liver disease, or other potential indications. Although never a routine procedure, more than 900 LTs are performed annually in the UK (NHS Blood and Transplant (NHSBT), 2022a), with approximately 36 000 worldwide per year (Global Observatory on Donation and Transplantation, 2022). Despite this level of activity, a mismatch between supply and demand persists, with 400 to 500 patients awaiting LT at any one time in the UK (NHSBT, 2022a).
Organisation of transplants in the UK is regional, with post-transplant patients normally followed up in local centres. If unwell, they will likely present to primary or secondary care services prior to referral on to tertiary transplant units if indicated. Excellent, and continuously improving, survival rates post-transplant mean that there is a large population of LT recipients within the general community. It is therefore important that advanced clinical practitioners (ACPs) are aware of some of the key issues associated with the transplant assessment process, the appropriate clinical management of transplant patients and develop an understanding of some of the specific complexities discussed in this article.
Liver transplantation in the UK
Seven LT units offer assessment and subsequent LT services in the UK (see Box 1). These units are often associated or combined with other organ transplant services due to significant crossover in the management of this specialist group of patients. If a patient is considered a potential candidate for transplantation and meets the criteria, they will be referred to a transplant unit to undergo a thorough assessment process (discussed below).
Box 1.Adult liver transplant units in the UK
- Birmingham (Queen Elizabeth Hospital)
- Cambridge (Addenbrooke's Hospital)
- Edinburgh (Royal Infirmary)
- Leeds (St James's University Hospital)
- London (King's College Hospital)
- London (Royal Free Hospital)
- Newcastle (Freeman Hospital)
Source: NHS website, 2022
Clinical conditions that allow activation on to the UK elective waiting list for LT (the selection criteria) are listed in Table 1, including key disease aetiologies. Conditions may broadly be placed into three categories: chronic liver disease (CLD); hepatocellular carcinoma (HCC); and variant syndromes. Patients with acute liver failure may also be candidates for transplantation, but attain eligibility through different criteria (NHSBT, 2019a).
Table 1. Eligibility criteria for listing for liver transplantation in the UK (excluding acute liver failure aetiologies and criteria)
| Chronic liver disease (UKELD ≥49) | Hepatocellular carcinoma (proven on 2 modalities of imaging) | Variant syndromes (UKELD <49) (non-exhaustive list) |
|---|---|---|
|
|
|
Contraindications
|
Key: UKELD=UK End Stage Liver Disease
Source: adapted from Millson et al, 2020a; NHSBT, 2019aThe largest category of patients on the waiting list fall within the CLD group. This cohort of patients will have been assessed to have a UK End-stage Liver Disease (UKELD) score of ≥49 (see Box 2) (Barber et al, 2011; NHSBT, 2022b). The UKELD score is a composite score of laboratory-assessed blood test parameters (bilirubin, international normalised ratio (INR), creatinine and sodium), with worsening liver function reflected as a higher calculated UKELD score. A score of 49 corresponds to a 9% chance of death within 1 year, and was thus selected as the threshold level to become eligible for LT in the UK, as the approximate corollary of survival at 1 year post-LT. To illustrate further, a calculated UKELD score of 60 correlates to a 50% 1-year mortality risk.
Box 2.UK End Stage Liver Disease (UKELD) score
- UKELD score: ≥49 confers eligibility for transplantation listing for liver failure/chronic liver disease. Higher UKELD scores correlate with increased severity of disease and associated increased mortality
- Formula: UKELD score = 5.395 × In (INR) + 1.485 × In (creatinine, μmol/litre) + 3.13 × In (bilirubin, μmol/litre) – 81.565 × In (serum sodium, mmol/litre) + 435
- In clinical practice, an online calculator is routinely used to derive a UKELD score
Key: INR=international normalised ratio; In=natural logarithmSource: Neuberger et al, 2008; Barber et al, 2011; NHSBT, 2019a; 2022b.
Once activated on the transplant waiting list, organs are offered to recipients on a named patient basis, UK wide. Prioritisation is according to risk of death without transplantation. A composite score, the ‘Transplant Benefit Score’ (TBS) (see Table 2), is applied to match utility of graft use to the clinical need of patients (University of Edinburgh, 2018). The TBS score is calculated from 21 recipient and 7 donor characteristics, generating an overall score, with higher scores afforded greater priority on the waiting list (University of Edinburgh, 2018; NHSBT, 2019b).
Table 2. Components of the Transplant Benefit Score
| Recipient characteristics | Recipient characteristics (continued) | Donor characteristics |
|---|---|---|
|
|
|
Key: *=splittable graft (a single donor organ may be utilised for two recipients by ‘splitting’, suitability for this depends on various additional factors)
BMI=body mass index; DBD=donation after brainstem death; DCD=donation after circulatory death; INR=International normalised ratio; LT=liver transplant
Source: University of Edinburgh, 2018Additionally, blood group compatibility and a near size match between donor and recipient are considered in this allocation. Unlike some other organs transplanted, human leukocyte antigen (HLA) matching is not generally of significance. Survival post-transplantation is excellent, with patient survival of ~92%, 84%, and 76% at 1, 3 and 5 years, respectively. Graft survival is slightly lower, reflecting the need for re-transplantation in some patients, at around 90%, 80% and 73% at 1, 3 and 5 years (Craig and Heller, 2021).
Finally, as mentioned above, selected patients experiencing acute liver failure (previously referred to as fulminant hepatic failure) may also be eligible for transplantation. However, aetiologies of liver injury, criteria for listing and prioritisation on the waiting list are very different, as is pre-transplant management and determination of prognosis, and are not further considered in this article.
Assessment of suitability
Following referral to a transplant unit, assessment of suitability for transplant is conducted.
Historically, this has generally involved a short inpatient stay for the potential LT recipient, but increasingly may now be conducted on an outpatient basis for selected candidates. The aim of this process is to fully assess both physical and psychosocial suitability for the potential LT procedure. A specialist nursing role, that of the transplant co-ordinator, is key to the process and provides a thread of continuity throughout a patient's LT journey. The transplant co-ordinator will often be the first person from a transplant unit to make contact with potential recipients to arrange assessment, counsel them around the LT process during assessment, lead the process of ongoing follow up if listed and call them in once an organ becomes available.
On admission for assessment, medical clerking and history taking is targeted at eliciting the chronology of the disease process, significant decompensating events from a hepatology perspective, and other comorbid conditions that may impact on the transplant decision. Clearly, patients will arrive at the unit with a relatively secure diagnosis, although new findings during the assessment process are not uncommon (for example new HCC demonstrated on imaging). Part of the assessment process is to ensure the referring diagnosis is accurate and to exclude any reasonable possibility of reversibility in condition. Consideration of potential contraindications to transplant is also a critical part of the process (Table 3).
Table 3. Contraindications to liver transplantation
| Absolute contraindications | Relative contraindications |
|---|---|
|
|
Key: BMI=body mass index
Source: adapted from NHS Blood and Transplant, 2019a; Millson et al, 2020aAn important guiding principle in consideration of LT is that anticipated length of life without transplantation should be less than that reasonably expected to be obtained with LT. Additionally, a patient's predicted 5-year survival post-transplant should be >50%. This makes consideration of comorbidity and pre-transplant functional status of candidates particularly important at the assessment stage. Patients with CLD often present with a significant range of clinical findings, including, for example, jaundice, ascites, encephalopathy, asterixis, hepatic hydrothorax, clubbing, sarcopenia and splenomegaly.
Once accepted for assessment, patients should be counselled to expect to undergo a range of investigations in order to ascertain suitability (Box 3), as well as being assessed by various members of the wider transplant team (Box 4). The assessment process is often a challenging one for potential recipients, owing to the inevitable uncertainty around outcomes of the process, therefore supporting patients through this journey should be considered a nursing priority.
Box 3.Investigations potentially undertaken in order to assess suitability for liver transplantation*
- Comprehensive range of blood testing including blood-borne viruses, immunological profile, blood group typing
- Respiratory function testing
- Transthoracic echocardiogram
- Electrocardiogram
- Formal cardiopulmonary exercise testing (‘CPET/CPEX’) (normally a static bike test)
- Cross-sectional imaging (commonly CT alone if CLD with no HCC, CT and MRI if HCC); If candidates are potentially being listed due to HCC, this requires to be proven on 2 modalities of imaging
- Endoscopic surveillance +/- treatment of varices
*may be as inpatient or outpatient tests, and may be conducted by referring centres prior to patient attending for assessment at a transplant centreCLD=chronic liver disease; CPET/CPEX=cardiopulmonary exercise testing CT=computed tomography; HCC=hepatocellular carcinoma; MRI= magnetic resonance imagingSource: Millson et al, 2020a; NHSBT, 2019a
Box 4.Key elements of the multidisciplinary assessment of a liver transplant candidate
- Anaesthetic review
- Hepatology review
- Surgical review
- Psychological review dependent on underlying aetiology (psychiatry/alcohol liaison team)
- Dietetic assessment
- Social work input
- Other specialty review depending on comorbidity and risk factors, for example diabetes, endocrinology, cardiology, respiratory, neurological
Source: Millson et al, 2020a; NHSBT, 2019a
Psychosocial considerations are central to the decision to list for LT, particularly if a history of alcohol excess or illicit drug use is noted. It is generally the expectation that abstinence has been maintained, and confirmed before referral. It is notable that a minimum duration of abstinence from alcohol is not specified in national guidance, although shorter periods of abstinence are recognised as associated with increased risk of relapse (NHSBT, 2019a). Repeated, documented, non-adherence to advice to abstain from alcohol represents an absolute contraindication to referral for transplant assessment.
A period of abstinence is important as it allows practitioners to both gauge a patient's ability to maintain abstinence, and to assess whether sufficient recovery of the liver may render LT unnecessary (Millson et al, 2020a). Although in the majority of cases this will have been confirmed by the referring team, in some situations the trajectory of disease may necessitate earlier referral and assessment.
A key consideration during assessment is to ascertain risk of relapse, and one of the key predictors of this is prior length of maintained abstinence. Additionally, where there is a history of non-compliance with medications or engagement with follow-up care, psychological assessment may be a crucial factor.
The assessment process culminates in a multidisciplinary team meeting to decide on the most appropriate management of each potential candidate. Potential outcomes may include: ‘watchful waiting’; recommendation of immediate listing for transplantation; recommendation of alternative therapies; or decline of LT if the patient is considered not to be a suitable candidate. Potential alternative therapies include shunt placement (transjugular intrahepatic porto-systemic stent or TIPSS) as treatment for refractory ascites (Tripathi et al, 2020), or loco-regional therapies for treatment of HCC. Once activated on the waiting list, patients may be offered LT at any point, with allocation of potential donor grafts according to TBS.
The transplant operation
When called in for LT, patients will be reviewed to ensure there is no new deterioration in their condition that would render transplant unsuitable, such as a new infective complication or development in HCC size or number. The majority of LT procedures performed in the UK use cadaveric donors (~90%), with the remaining 10% of transplantation from live donors, primarily from adult to child (Millson et al, 2020b). The majority of grafts implanted are whole liver grafts, though either ‘reduced’ or ‘split’ liver grafts may be used for select patients. Most LT operations replace the diseased native liver with the donor graft in the same position, described fully as an ‘orthotopic’ LT.
Assuming no acute issue is identified, patients will proceed to theatre for transplantation, in an operation that can be complex and prolonged. Patients will routinely be managed in an intensive care setting initially, intubated and ventilated until early Doppler imaging of the graft and close monitoring of blood parameters demonstrate adequate graft function. An early, severe complication may be ‘primary non-function’ of the implanted graft, necessitating rapid re-transplantation. The pathology of this remains unclear, and it is a rare complication (4-6%) (Millson et al, 2020b; Eghtesad et al, 2010). Assuming patients improve and progress adequately, they will be extubated and care progressed to high dependency, then ward environments as recovery continues. Duration of intensive care support varies, but extubation within 24 hours of transplantation is common.
Immunosuppression and prophylactic medications are generally instigated early in recovery once a safe oral route is established, with alternate routes for medication delivery considered if necessary. Although immunosuppression regimens vary across centres, there is rarely a requirement for initiation of immunosuppression before the LT operation. Adherence to the prescribed medication regimen is central to maintaining adequate graft function, and patients will have extensive input to ensure that they are fully conversant with their new medication regimens prior to discharge from hospital. The role of the specialist pharmacist is often central to this process. Overall length of hospital stay post-LT is hard to predict, as different centres will have varying processes in place for follow up, but it seems reasonable to suggest that 10 to 21 days post-LT would be typical. Additionally, pre-transplant condition, underlying comorbidity and any postoperative complications encountered will affect duration of hospitalisation.
Recovery is marked by wide interdisciplinary working to optimise the LT recipient's condition, with close attention to physiotherapy, dietetic, pharmacy and specialist nursing support. Typically, there will be daily consultant-level input from transplant hepatology specialists, transplant surgeons and anaesthetic colleagues.
Before discharge, transplant co-ordinators will meet with patients and families to ensure understanding of their new medication regimen and particular lifestyle changes recommended in order to maximise longevity of the liver graft and minimise risk of complications (Millson et al, 2020b).
Initial follow up will typically be directly with the transplant unit, normally weekly for a period of 6 weeks, with frequency of follow up reducing as patients continue to recover. Follow up is maintained with LT recipients on a lifelong basis, at decreasing frequency as time from transplant extends, assuming no complications are encountered.
If complications do occur post-LT, it may be that the LT recipient presents to local healthcare services, distant from their LT centre. In this situation, a low threshold for contacting the transplant centre for discussion would generally be adopted.
Key medications and prescribing considerations for LT recipients
Immunosuppression
Establishment and maintenance of an effective, appropriate immunosuppression regimen is central to longevity and ongoing function of the LT graft. Choice of immunosuppression regimen is challenging and highly individualised; however, certain elements are relatively universal.
The majority of LT recipients will be started on a triple agent combination, composed of a calcineurin inhibitor (CNI), anti-metabolite agent and corticosteroid. As acknowledged by Mukherjee and Mukherjee (2009), this multi-modal approach targets different sites of T-cell activation, allowing lower doses of each individual drug while optimising overall effect, and minimising side effects (Table 4).
Table 4. Commonly used transplant medications and key side effects
| Drug | Adverse effects |
|---|---|
| Tacrolimus (CNI) | Nephrotoxicity, diabetes, hyperkalaemia, metabolic acidosis, hypertension, hyperlipidaemia, neurotoxicity, tremor, increased infection risk, gout, hypomagnesaemia, insomnia |
| Ciclosporin (CNI) | Nephrotoxicity, diabetes, hyperkalaemia, hypertension, neurotoxicity, hyperlipidaemia, metabolic acidosis, hypertrichosis, gingival hyperplasia |
| Mycophenolate | Myelosuppression, gastrointestinal side effects, increased susceptibility to viral infections (CMV/HSV), teratogenic effects |
| Corticosteroids | Diabetes, hypertension, obesity, osteoporosis, avascular necrosis, growth retardation, Cushingoid facies, psychosis, poor wound healing, adrenal suppression, cataract formation, muscle weakness, skin thinning, acne, headaches, peptic ulceration, pancreatitis, sodium retention, fluid retention, potassium depletion |
Key: CNI=calcineurin inhibitor; CMV=cytomegalovirus; HSV=herpes simplex virus
Source: adapted from Pillai and Levitsky, 2009; Millson et al, 2020a; Joint Formulary Committee, 2021A significant issue within the field of transplantation remains non-adherence with medication regimens, cited at up to 40% in some studies (Morrissey et al, 2007). Options for simplification of regimens by use of, for example, prolonged-release preparations should be explored and may be best supported by specialist pharmacists within a clinic setting.
The most widely used CNIs are tacrolimus and ciclosporin, with tacrolimus more commonly used in the UK. These medications have a narrow therapeutic range, a significant side effect profile, and multiple drug–drug interactions, necessitating close monitoring of serum levels during initiation, then regular surveillance once established. If underdosed, there is a significant risk of graft rejection. The individual pharmacokinetic and pharmacodynamic properties of different manufacturers' preparations mean that differing formulations cannot be considered bio-equivalent and should not be switched without expert monitoring and, unusually, should be prescribed by brand name, rather than generically (Medicines and Healthcare products Regulatory Agency (MHRA), 2017). Unacceptable side effects, including renal impairment, may prompt a switch to an alternate CNI, generally after consideration of dose alteration of anti-proliferative and steroid agents.
Common anti-metabolite medications include azathioprine and varying preparations of mycophenolate. Initial choice is dependent on the centre and individual risk profiling. Generally, mycophenolate is preferred if pre-existing renal impairment is present, as its more immunosuppressive profile allows for lower dosing of CNI. Similarly, new renal compromise may trigger a switch from azathioprine. A common side effect of mycophenolate is gastric upset, which may limit its use or necessitate switching between preparations. Additionally, mycophenolate is a recognised teratogen, and should be discontinued if LT recipients or partners are planning pregnancy.
The third component of the immunosuppression regimen is corticosteroids, which are valuable for their enhancement of overall immunosuppression load. However, their use is normally rapidly titrated and often discontinued in the LT context in order to minimise the well-documented adverse side effect profile. In some cases, early steroid-induced psychosis may prompt more rapid titration. An additional significant side effect encountered is steroid-induced diabetes, or worsening of pre-existing glycaemic control, which may be a long-term effect.
Post-transplant prophylaxis medications
LT recipients will start on a spectrum of prophylaxis medications at, or soon after, transplantation. These will commonly include gastric and bone prophylaxis (in the context of steroid use), as well as infection prophylaxis targeted against key opportunistic infections (commonly including: Pneumocystis jerovichii pneumonia; cytomegalovirus disease; fungal disease). If the transplant was conducted for hepatitis B or C, consideration will additionally be given to medication to reduce risk of recurrence or actively treat, as appropriate. Routine thromboprophylaxis will be given as an inpatient, but is not routinely continued at discharge, unless there is concern for vascular patency due to pre-existing pro-thrombotic tendencies. Analgesia will be required on a short-term basis, but the patient should be weaned as rapidly as practicable.
Drug interactions
ACPs who are not employed in hepatology or transplant roles are unlikely to be required to make dose adjustments to immunosuppression medications without direct involvement of the transplant team. However, given the increasing number of transplant recipients in the wider community, it is likely that prescribers will encounter this group of patients and thus need to have an awareness of potential drug interactions that may impact on their prescribing decisions.
Tacrolimus and ciclosporin, in particular, have many noted drug interactions, with in excess of 180 specific incidences listed in a common drug interaction resource (Joint Formulary Committee, 2021). The impact of these interactions should not be underestimated; interactions that increase exposure to CNIs may lead to significant toxicity, while those decreasing exposure to the drug may expose patients to increased risk of rejection of their liver graft. In general, if starting a new drug for an LT recipient, prescribers are advised to use a recognised drug interaction database to avoid such issues. Further reference to pharmacist colleagues, or ultimately the responsible transplant centre, may be necessary where there is any doubt or uncertainty around these decisions. Some of the more common and important potential drug interactions are included in Table 5, but this is indicative only and should not be considered exhaustive.
Table 5. Common and clinically important drug interactions with ciclosporin and tacrolimus (calcineurin inhibitors)
| Class of drugs | Interacting agents | Effect on immunosuppressant level |
|---|---|---|
| Anticonvulsants | Carbamazepine, phenobarbital, pentobarbital, phenytoin | Potential for significant decrease in serum level of ciclosporin and tacrolimus(Effect on level may occur over weeks) |
| Antimicrobials | ||
| Macrolide antibiotics | Azithromycin, clarithromycin, erythromycin | Potential for significant increase in serum levels of ciclosporin and tacrolimus |
| Antifungals | Fluconazole, itraconazole, voriconazole, posaconazole | Potential for significant increase in serum levels of ciclosporin and tacrolimus |
| Antimalarials | Mefloquine, quinine, quinidine | Potential for significant increase in serum levels of ciclosporin and tacrolimus |
| Antimycobacterials | Rifabutin, rifampicin | Potential for significant increase in serum levels of ciclosporin and tacrolimus |
| HIV and hepatitis C anti-retrovirals (Note: protease inhibitor concentrations may be increased by concomitant use of ciclosporin) | Atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, tipranavirEfavirenz, etravirine, nevirapine, tipranavir | Potential for significant increase in serum levels of ciclosporin and tacrolimusPotential for significant decrease in serum level of ciclosporin and tacrolimus(Note differing sources cite potential for increase or decrease in serum levels with tipranavir) |
| Benzodiazepines | Clonazepam, diazepam, midazolam | Potential for increased benzodiazepine concentrations with ciclosporin |
| Cardiovascular | ||
| Antiarrhythmics | Amiodarone, lidocaine (systemic), quinidine | Potential for increased serum level of ciclosporin and tacrolimus |
| Anticoagulants (direct factor Xa inhibitors) | Apixaban, rivaroxaban | Potential for increased anticoagulation levels |
| Calcium channel blockers | Diltiazem, verapamilAmlodipine, felodipine, nifedipine | Potential for increased serum ciclosporin and tacrolimus levelPotential for significant increase in tacrolimus level |
| Statins | Atorvastatin, rosuvastatin, pravastatin, simvastatin | Exposure to statin markedly increased with ciclosporin − increased risk of statin toxicity including myotoxicity |
| Other cardiovascular medications | Carvedilol, dipyridamole, propranolol | Potential for increased serum ciclosporin and tacrolimus level |
| Dietary | Grapefruit juice, grapefruit | Potential for increased serum ciclosporin and tacrolimus level |
| Anti-gout | Allopurinol | Potential for marked increase in serum ciclosporin level |
| Colchicine | Increased risk of colchicine toxicity with tacrolimus and ciclosporin | |
| Herbal preparations | St John's Wort | Potential for marked decrease in serum ciclosporin and tacrolimus levels |
| Hypnotics | Zopiclone, zolpidem | Increase in hypnotic concentration with ciclosporin |
| Immunosuppressants | SirolimusMycophenolate mofetil | Increased risk of renal, haematological and other toxicities in combination with tacrolimus and ciclosporinDecreased mycophenolate concentration with ciclosporin |
Post-transplant complications
LT recipients are prone to a variety of complications after surgery, which may present as immediate, short-term and longer term issues. The severity of such complications varies from mild to those which may threaten the transplant graft or life of the LT recipient. ACPs may encounter this group of patients in primary or secondary care, where prompt recognition of, and attention to, such complications may mitigate more severe outcomes.
Broadly, complications may be categorised into four fields: infection, immunological (rejection), vascular and biliary. Additionally, LT recipients will have an increased lifetime risk of certain neoplasms, some with an infective component (for example, Epstein-Barr virus mediated post-transplant lymphoproliferative disorder). Finally, there is a risk of recurrence of primary disease (primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)), for example (Schreibman and Regev, 2006; Ueda et al, 2017), or recurrence of HCC, which may prompt the need for consideration of re-transplantation.
Infection
By definition, immunosuppression confers an increased risk of infective complications, either from de novo infectious agents, re-activation of latent disease, operative infective complications or potentially transmissible disease from the donor. Around two-thirds of all LT recipients will develop an infective complication in the first year post-transplant (Eghtesad et al, 2010), and infection remains one of the main causes of morbidity and mortality in the LT population.
LT recipients routinely receive prophylaxis against fungal, viral and bacterial infection; however, specific regimens vary according to the transplant centre (Chelala et al, 2015). Recipients are also counselled regarding strategies to minimise exposure to infection, particularly in the early postoperative period, when immunosuppressive burden is highest.
Of note, response to infection may be altered, with pyrexia not necessarily as prominent a feature as for the immuno-competent population (Chelala et al, 2015). Infection should therefore routinely be considered and actively excluded in the unwell transplant recipient. Early and liberal sampling for potential infective sources will allow closer targeting of antimicrobial therapy as soon as practicable. Knowledge of pre-transplant status may assist in this process, for example, any previous exposure to tuberculosis would confer a lower threshold for consideration of this agent as a potential infective source. Similarly, knowledge of pre-transplant ascites may prompt early diagnostic sampling to exclude an intra-abdominal source. In general, there will be a low threshold for cross-sectional imaging in this patient group in order to exclude any intra-abdominal nidus of infection.
Immunological complications
All transplant recipients are managed according to a balance of risk of rejection versus infection, and it can be challenging to obtain this optimal balance. Rejection is a much feared complication among recipients, but is in fact common (15-25% of LT recipients) and generally readily treatable (Choudhary et al, 2017). Episodes of acute rejection do not generally impact upon long-term graft outcomes.
Rejection may present as a hyper-acute, antibody-mediated, early manifestation and while described in the literature, is uncommon in LT recipients (Della-Guardia et al, 2008). More frequently, rejection is seen in either acute or chronic forms, with the acute form being much more common, and generally occurring within the first 90 days post-LT. It can, however, present much later in the life of a graft. Acute rejection (AR) may also be described as ‘ACR’ (acute cellular rejection) or ‘TCMR’ (T-cell mediated rejection) in line with internationally recognised criteria for histopathological determination of rejection in LT (Clouston and Hubscher, 2018). Rejection will generally be considered if new derangement in markers of liver function is seen (particularly elevated transaminases), and may also present with clinical features including fever, new jaundice, fatigue and graft tenderness (Millson et al, 2020b) and is confirmed on liver biopsy. Other potential causes for derangement in liver function will also require exclusion (such as infection or vascular complications), generally concurrent with or before biopsy being undertaken, as this is not without associated risks. As with all presentations, clinical history is crucial here, particularly where there is any uncertainty around a patient's concordance with taking their prescribed immunosuppression.
With AR, treatment involves increasing the overall immunosuppressive load, with the most common being a short course of intravenous steroids, typically pulsed over 3 days, followed by appropriate incrementing of routine immunosuppression. However, as described above, infective complications may hinder a clinician's ability to increase immunosuppression, as may bone marrow suppression as a result of medications, making management particularly challenging in some cases.
Chronic rejection (CR) is also determined histopathologically, is also immune mediated, but is defined by bile duct and vascular damage that may be irreversible. Its occurrence has diminished significantly following the introduction of increasingly effective immunosuppression regimens, with graft failure from CR now occurring in <2% of cases (Clouston and Hubscher, 2018). Management depends on severity and current treatment regimens. Increased immunosuppressive load may produce improvement, but this is hard to predict and some of this group of patients will progress to needing re-transplantation.
Vascular complications
The liver's dual blood supply, from the hepatic artery and portal vein, necessitates multiple surgical anastomoses at the time of transplantation, with the concurrent risk of bleeding or thrombotic complications. In the immediate postoperative period, bleeding issues are relatively common (reported in 7-15% of patients) and may be managed by a return to theatre for re-laparotomy and control (in approximately 50% of cases) (Eghtesad et al, 2010). A key early vascular complication is that of hepatic artery thrombosis (HAT), which remains a leading cause of graft failure and is actively screened for in the early postoperative period (normally via day 0 or day 1 Doppler ultrasound scanning). HAT is seen in up to 12% of LTs (Craig and Heller, 2021), and leads to biliary ischaemic complications such as bilioma formation and biliary structuring. Early HAT may be conducive to interventional radiology salvage, but will normally require re-transplantation.
Biliary complications
As part of the transplant operation, bile duct continuity from donor to recipient is established, either through ‘end-to-end’ direct anastomosis, or via choledochojejunostomy in cases where pre-existing bile duct pathology may impact upon the quality of the anastomosis (for example in primary sclerosing cholangitis), or in re-transplantation. Biliary complications are cited as the most common surgical complication post-transplant, with an incidence of 15-30% (Eghtesad et al, 2010; Craig and Heller, 2021).
The biliary anastomosis is prone to several complications, including bile leak, stricturing, and cholangitis. Bile leak will normally be an early finding, and is associated with significant abdominal pain. Investigation would normally be via ultrasound scan or cross-sectional imaging, with magnetic resonance imaging as the preferred modality (Craig and Heller, 2021). If bile leak is present these collections tend to be sterile, but if infected, can be challenging to manage. Small leaks may respond to conservative management, but larger volume problems are likely to require direct control (interventional radiology or endoscopic or direct surgical control).
Bile-duct stricture should be considered in the context of an obstructive pattern of liver function test deterioration, and represents the most common bile-duct complication post-LT. Strictures may arise due to technical aspects of the operation, or due to fibrosis, ischaemia or disease recurrence as a later complication, and may be at the site of anastomosis, or non-anastomotic. Endoscopic intervention (via endoscopic retrograde cholangio-pancreatography (ERCP) techniques), with stenting if possible, is usually the first line of treatment attempted, but may not be possible in longer, tighter strictures, leading to the potential need for re-transplantation.
Conclusion
Effective care of the LT recipient is a complex, truly multidisciplinary endeavour, with excellent outcomes anticipated for the majority of recipients. However, there are numerous potential complications faced by LT recipients, both in the short and longer term. The requirement for lifelong immunosuppression confers an increased risk of infection and some malignancies in liver transplant recipients. Additionally, LT recipients may be prone to a variety of surgical complications, either acutely or presenting in a more chronic fashion.
The ACP may come into contact with patients facing potential LT, or LT recipients, at varying stages in their clinical course, in multiple clinical contexts. Therefore, an understanding of potential complications, and recognition of the need for early escalation and discussion with a specialist transplant centre, may mitigate potential adverse outcomes.
Finally, prescribing for the LT recipient is complex, with multiple significant drug interactions and potentially graft- or life-threatening complications from missed or incorrect dosing. Knowledge of key common medications, their side effect profiles, and important drug interactions, will aid in the effective management of this group of patients.
KEY POINTS
- Liver transplantation is a major surgical undertaking, but in a carefully selected population, provides excellent outcomes in terms of prolongation of life and improvements in quality of life
- The role of the advanced clinical practitioner in primary or secondary care may focus upon identifying potential candidates for transplantation and ensuring timely discussion and referral
- Referral for consideration of transplantation and subsequent assessment at a transplant unit, is a complex, challenging process, involving multiple members of an extended multidisciplinary team
- Requirement for lifelong immunosuppression confers an increased risk of infection and some malignancies
- Prescribing for the liver transplant recipient is complex, with multiple significant drug interactions and potentially graft- or life-threatening complications from missed or incorrect dosing
CPD reflective questions
- Consider how you could provide a person-centred approach to support a patient who is considering a liver transplant as a treatment option
- Reflect upon common medication prescriptions that you encounter in your practice and their potential for drug interactions with immunosuppressant medications. How would you manage patients you encounter with such potential interactions?
- Consider how to support a liver transplant patient who comes under your care, particularly in relation to prolonging graft life and function