Chapter 89: Liver Transplantation

Historical Perspective

Thomas E Starzl first attempted liver transplantation (LT) in 1963; in the first five transplants no patient survived more than 23 days (Figure S89.1). In 1967, Starzl had achieved prolonged survival (more than 1 year), stimulated by Roy Calne, who used a combination of antilymphocyte serum, azathioprine and prednisolone. The first LT outside the USA was performed in Cambridge, UK, by Roy Calne in 1968 (Figure S89.2). Throughout the 1970s, LT remained a hazardous procedure that frequently failed as a result of technical and immunological complications. In 1979, Roy Calne used ciclosporin for the first time in two LT patients and showed improved outcomes. By 1989, Starzl and colleagues reported a series of 1179 consecutive LTs with a survival rate of 73% and 64% at 1 and 5 years, respectively. With the introduction of tacrolimus in 1990, the first year patient and graft survival improved to 82% and 75%, respectively (Figure S89.3). Since then, the results have progressively improved as a result of better patient selection, better organ preservation, refinements in the surgical technique, improved immunosuppression and advances in per- and postoperative management. A few milestones of LT are listed in Table S89.1.

LT is now well established as an effective treatment for selected patients with end-stage liver disease as a routine procedure with good outcome. However, transplant activity is still limited by the shortage of donor organs.

TABLE S89.1 Milestones in liver transplantation.

1963	Thomas Starzl performed the first human liver transplantation (Denver, CO, USA)
1978	Roy Calne introduced ciclosporin into clinical practice (Cambridge, UK)
1981	Henri Bismuth and Didier Houssin reported the first reduced size liver graft (Paris, France)
1983	NIH Consensus Conference established liver transplantation as an acceptable treatment for end-stage liver disease – ‘clinical service’ rather than experimental procedure (USA)
1987	Folkert Belzer and colleagues developed University of Wisconsin (UW) solution – a new liver and pancreas preservation solution (Wisconsin, USA)
1988	Rudolf Pichlmayr performed the first splitting of a donor liver for use in two recipients (Hanover, Germany)
1989	Thomas Starzl demonstrated clinical efficacy of FK506 (tacrolimus) (Pittsburgh, PA, USA)
1989	Russel Strong performed the first successful paediatric living donor liver transplantation (Brisbane, Australia)
1993	The Shinshu group performed the first successful adult living donor liver transplantation (Matsumoto, Japan)
2002	Daniel Cherqui performed the first laparoscopic donor left lateral sectionectomy for paediatric living donor liver transplantation (Paris, France)
2006	Alan Koffron performed the first laparoscope-assisted donor right hepatectomy for adult living donor liver transplantation (Illinois, USA)

Indications and Patient Selection

The indications for liver transplantation (LT) fall into four groups:

1. chronic liver disease (CLD);
2. acute liver failure (ALF);
3. metabolic liver disease (including liver-based inborn errors of metabolism);
4. primary hepatic malignancy (hepatocellular carcinoma [HCC], hepatoblastoma).

The most common indication for LT is decompensated CLD (Table 89.1). In adults the most common causes are alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), chronic viral hepatitis (hepatitis B virus [HBV] and hepatitis C virus [HCV]), autoimmune liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes) and cirrhotic metabolic liver diseases (Wilson’s disease). The specific frequencies of these aetiologies depend on geographical variations. In the last two decades hepatitis-related CLD (HBV and HCV) was the most common indication for LT. However, with universal vaccination for HBV and newer treatment options for HCV and with increasing obesity in affluent countries, NAFLD is projected to become the most common indication for LT in the future. In children, who account for around 10–15% of all LTs, biliary atresia is the most common indication for transplantation. ALF requiring transplantation on an urgent basis accounts for approximately 10% of LT activity and is usually drug induced or viral (e.g. paracetamol overdose in the UK). There are a variety of non-cirrhotic metabolic diseases for which transplantation offers the prospect of cure, including urea cycle defect, oxalosis and familial hypercholesterolaemia. Primary hepatic malignancy is more common in patients with cirrhosis, especially viral-induced liver disease and NAFLD, and may be best treated by transplantation when advanced liver disease precludes liver resection because of the risk of postoperative liver failure or when the tumour is multifocal as a result of field changes in the cirrhotic liver that predispose to recurrence or further primary malignancies.

LTs are usually performed between ABO blood group-compatible donor–recipient pairs. Histocompatibility matching, as in kidney transplantation, has not been necessary in LT as the liver is considered a more immunologically privileged organ. In countries where living donor liver transplantations (LDLTs) are performed in large numbers because of a lack of deceased donor organs, there has been a recent increase in the number of ABO-incompatible LTs when there is no blood group-compatible donor available. However, there is an increased risk of infection owing to a higher immunosuppression protocol and a higher incidence of antibody-mediated rejection with this type of transplantation.

Potential candidates undergo a comprehensive multidisciplinary assessment, including hepatologists, transplant surgeons, anaesthetists, specialist nurses in LT, drug and alcohol rehabilitation services, dietician, psychologists and specialists from other clinical disciplines where indicated. Three underlying principles dictate which patients should be referred for, and potentially undergo, LT. First, the recipient should have irreversible liver disease (acute or chronic) that is expected to be fatal without transplantation. Second, the patient should have sufficient reserve to survive the operative and perioperative period. Finally, the candidate should be expected to have significant survival (>50% at 5 years) and quality of life benefit from LT.

Registration for LT therefore requires patients to meet minimum listing criteria within four broad indications: ALF, CLD, variant syndromes (e.g. refractory ascites, chronic encephalopathy, hepatopulmonary syndrome, recurrent cholangitis) and primary liver cancer (Table 89.1). The absolute and relative contraindications for LT are listed in Table S89.2.

TABLE S89.2 Absolute and relative contraindications for liver transplant.

Absolute

Severe extrahepatic disease with predicted mortality >50% at 5 years Severe cardiac and/or pulmonary disease Severe pulmonary hypertension (mean pulmonary artery pressure >45 mmHg) Active alcohol or substance abuse Active extrahepatic infection/uncontrolled sepsis Lack of psychosocial support or inability to comply with medical treatment Liver cancer outside transplant criteria Active extrahepatic malignancy

Relative

Absent or inadequate psychosocial support Persistent non-adherence to treatment/follow-up Severe psychiatric disorder Morbid obesity Severe malnutrition

TABLE 89.1 Conditions that are considered for liver transplantation in adults and children.

TABLE 89.1 Conditions that are considered for liver transplantation in adults and children.
	Aetiology in adult	Aetiology in children
Acute liver failure (severe acute impairment of liver function with encephalopathy that occurs within 8 weeks of the onset of symptoms and no recognised underlying chronic liver disease)	Drugs (paracetamol overdose) Hepatitis A and E Acute Wilson’s disease Autoimmune hepatitis Acute fatty liver of pregnancy	Drugs and toxins Hepatitis A and E Acute Wilson’s disease
Chronic liver disease (any diseases that cause cirrhosis and its associated complications)	Fatty liver disease: alcohol or non-alcohol related Chronic viral hepatitis B, C, D Autoimmune liver diseases: primary biliary cirrhosis, primary sclerosing cholangitis, overlap syndromes Genetic haemochromatosis Wilson’s disease α1-antitrypsin deficiency Secondary biliary cirrhosis	Biliary atresia α1-antitrypsin deficiency Autoimmune hepatitis Sclerosing cholangitis Caroli’s syndrome Wilson’s disease Cystic fibrosis Progressive familial intrahepatic cholestasis Alagille’s syndrome Glycogen storage disease (types 3 and 4) Tyrosinaemia type 1 Budd–Chiari syndrome Any aetiology leading to hepatopulmonary syndrome or portopulmonary hypertension
Variant syndromes (metabolic liver disease with life-threatening extrahepatic complications in children)	Intractable pruritus Hepatopulmonary syndrome Familial amyloidosis Primary hypercholesterolaemia Hepatic epithelioid haemangioendothelioma Recurrent cholangitis Nodular regenerative hyperplasia Hereditary haemorrhagic telangiectasia Glycogen storage disease Ornithine transcarbamylase deficiency Primary hyperoxaluria Maple syrup urine disease Porphyria Amyloidosis	Crigler–Najjar syndrome Urea cycle defects Hypercholesterolaemia Organic acidaemias Glycogen storage disease type 1 Maple syrup urine disease Porphyria
Liver tumours	Hepatocellular carcinoma Rarely – cholangiocarcinoma, neuroendocrine tumours, colorectal liver metastasis	Unresectable hepatoblastoma (without active extrahepatic disease) Unresectable benign liver tumours with disabling symptoms

Liver Transplantation for Hepatic Malignancy

As a general rule, malignancy in a solid organ is not an indication for transplantation. This is because of the risk of recurrence with immunosuppression post transplant; immunosuppression suppresses not only the host’s immunity preventing rejection of the transplanted graft but also the host’s immunity against cancer, which may cause rapid progression of disease after transplantation. However, LT is one area where a total hepatectomy in selected patients can remove the entire disease en bloc and give patients a full chance of cure. LT is widely indicated as a curative treatment for selected patients with HCC, haemangioendothelioma and hepatoblastoma. Because of its association with CLD, up to 25% of LTs in the UK are in patients with HCC. Using the size and number of HCCs on pretransplant imaging, there are a number of criteria that aim to select patients who have HCC with favourable tumour biology and hence a good outcome following LT. The two main staging criteria of HCC for the indication of LT are the Milan and the University of California San Francisco (UCSF) criteria.

The Milan criteria are defined as a solitary tumour ≤5 cm in diameter or three or fewer tumours ≤3 cm in diameter in the absence of extrahepatic or vascular spread. However, an expanded set of criteria, the UCSF criteria, allow patients with a solitary tumour smaller than 6.5 cm or patients with three or fewer nodules, with the largest lesion being smaller than 4.5 cm or having a total tumour diameter <8 cm without vascular invasion, to undergo LT. Current UK LT selection criteria for patients with HCC are an ‘expansion’ of the Milan criteria with a solitary tumour <5 cm in diameter, or up to five tumours all ≤3 cm, or a single tumour >5 cm and ≤7 cm in diameter if no progression over 6 months and α-fetoprotein (AFP) <1000 ng/mL. On the LT waiting list, HCC patients are allowed to have locoregional therapies, such as transarterial chemoembolisation (TACE) or radiofrequency ablation (RFA), and/or systemic therapies, such as kinase inhibitors (sorafenib, lenvatinib). If patients with HCC do not fall within the transplant criteria, then they are considered after appropriate downstaging of the tumour with locoregional therapy (Duvoux criteria) or are considered non-transplantable and hence taken down the palliative route.

With recent advances in diagnostic modalities and chemotherapeutic agents, LT has been carefully expanded to patients with other primary or secondary malignancies of the liver. Cholangiocarcinoma (CCA) has been an uncommon indication for LT for nearly three decades. Recently there has been more interest with wider adaptation of the Mayo protocol, which involves strict patient selection, intensive pre-LT chemoradiation therapy, staging laparoscopy to assess tumour spread and then transplantation. Five-year survival has been reported in the range of 55–65% for hilar CCA in patients with primary sclerosing cholangitis (PSC), who get these cancers more commonly than de novo CCAs.

Similarly, small intrahepatic CCAs in patients with background cirrhotic liver have 5-year survival in the range of 45–55% following LT. Unresectable colorectal and neuroendocrine liver metastases are considered ‘newer’ indications for LT and are still not accepted worldwide. Although recent results with LT for these indications are promising, caution takes precedence when expanding LT criteria for patients with cancer in order to avoid compromising patients awaiting LT for benign diseases with better prognosis.

Listing for Liver Transplantation

The allocation of liver grafts to patients with end-stage liver disease is dominated by three ethical principles: equity (need), utility (usefulness) and transplant benefit. The equity model gives prioritisation for sickest first, the utility prioritises the patient with the best expected outcome from transplantation and transplant benefit prioritises the patient with the greatest difference in expected survival with and without transplantation. The last balances both equity and utility and is expected to minimise mortality and maximise survival for the overall patients listed for transplant.

To list patients for LT, mathematical models are used to determine prognosis and for organ allocation. The model for end-stage liver disease (MELD), which was initially developed to predict survival in patients undergoing transjugular intrahepatic portosystemic shunt (TIPSS), is the most widely used scoring system and incorporates three widely available laboratory results: the international normalised ratio (INR), serum creatinine and serum bilirubin. Since 2008, the UK end-stage liver disease (UKELD) score, which is the addition of serum sodium to MELD, has proven to be an effective tool for selection of patients for LT and predicts mortality among patients on the LT waiting list. A minimum UKELD score of 49 is necessary to meet the criteria for listing on the LT waiting list, unless there are other indications such as variant syndromes or HCC (Table 89.1).

In 2018, NHS Blood and Transplant (NHSBT) introduced a new way of matching livers (National Liver Offering Scheme; NLOS) from deceased donors to adult patients on the LT waiting list. The new scheme matches livers on a national rather than a regional basis and helps to place the organ with the patient most likely to benefit from the offer. The new scheme of liver offering is considered to be more in depth and takes into account a total of 21 recipient and seven donor factors (Table S89.3). The patient with the best match will be shown at the top of the list and will have the highest transplant benefit score (TBS), thereby giving them the maximum ‘net benefit’ (difference in predicted survival with and without transplant).

The waiting times for LT depend on several factors, including the recipient’s blood group, their size or weight and their illness severity (i.e. UKELD or TBS score). For those electively listed for LT in the UK between April 2018 and March 2019, on average an adult patient waits 65 days for a transplant while paediatric patients wait an average of 77 days (NHSBT Annual Activity Report 2020). Patients on the LT waiting list are monitored regularly in outpatient clinics for any symptoms/signs of decompensation of liver disease, nutritional assessment, blood sampling and recalculating their risk scores. For patients with HCC, this will include 3-monthly AFP levels and imaging to assess if their tumours are still within the criteria for LT.

TABLE S89.3 Recipient and donor criteria used for calculating the transplant benefit score (TBS) used for ranking recipients on UK liver transplant waiting list.

Recipient criteria (21 factors)	Age, gender, hepatitis C, disease group, creatinine, bilirubin, INR, sodium, potassium, albumin, renal support, inpatient status, previous abdominal surgery, encephalopathy, ascites, time on waiting list, diabetes, maximum AFP level, maximum tumour size, two tumours and three or more tumours
Donor criteria (7 factors)	Age, cause of death, BMI, diabetes, donor type (DBD or DCD), blood group and splitliver criteria

Challenges and Potential Future Developments in Liver Transplantation

Donor shortage is the key issue in LT. The biggest challenge ahead for the LT community will be to implement strategies that will overcome donor organ shortage, but at the same time maximise the long-term outcomes of the grafts transplanted. Reducing the waiting list mortality will involve bridging the gap between the demand and availability. Optimising the organ quality using newer technologies such as machine perfusion and ‘growing livers in the lab’ are exciting prospects that could overcome the chronic organ shortage.

Machine perfusion

With the advances and improvements in outcomes in LT over the last four decades, there has been a focus on expanding deceased donor organs. Static cold storage (SCS) remains the standard-of-care preservation method in LT. This is achieved by cooling the liver to 4°C with preservation solution; this decreases cellular energy consumption by reducing the metabolic demand of the tissue. However, when these SCS organs are reperfused, there is a higher ischaemia–reperfusion injury owing to efflux of accumulated metabolic products formed during cold storage, resulting in a profound inflammatory immune response and causing damage to the hepatocytes and cholangiocytes, thereby leading to poor short- and long-term outcomes. One of the ways of reducing ischaemia–reperfusion injury is to perfuse the liver with cold solution (hypothermic machine perfusion; HMP) or warm blood (normothermic machine perfusion; NMP) with the aim of maintaining a healthy endothelium, replenishing adenosine triphosphate (ATP) and thereby improving quality. This allows the organs to be preserved for a longer period prior to transplantation, thereby addressing the logistics of LT. Further studies will be needed to explore the ideal perfusion method with the aim of improving longer term outcomes and avoiding biliary complications such as ischaemic cholangiopathy and to study viability markers to identify livers that will not function in the recipient, allowing liver-directed therapeutic interventions on the machine. In other exciting technology – in situ normothermic regional perfusion (NRP) – the blood supply to the abdominal organs after death is restored using extracorporeal circulation for a limited period before organ recovery. This leads to superior liver outcomes in DCD livers compared with conventional organ recovery, and may be an answer to the problem of ischaemic cholangiopathy.

Liver support devices

ALF has a high mortality in the range of 50–80%. Extra-corporeal liver support systems have the potential to provide temporary support to bridge patients with ALF to LT or spontaneous recovery.

The concept of the ‘artificial liver’ was first described in the 1950s by Sorrentino, who used fresh liver tissue homogenate to produce urea from ammonium chloride. Haemodialysis and haemofiltration as mechanisms of kidney dialysis were introduced in the early 1940s; these techniques were used as liver support devices in an attempt to remove toxins, but there was no improvement in patient survival. Since then, there have been multiple advancements in liver support devices, including the use of semipermeable membranes, peritoneal dialysis, the exchange of high plasma volumes, combining haemoperfusion with plasma perfusion, using resins such as activated charcoal for adsorption of toxic substances, and combining toxin adsorption with cation exchangers. The crucial factor in ALF has been the accumulation of low- to medium-molecular-weight toxic substances, which can cause multiple organ failure, brain swelling leading to encephalopathy, coma and eventually death.

Artificial liver support devices functionas ‘dialysis’ machines, which filter and adsorb toxic substances such as bilirubin, bile acids, metabolites of aromatic amino acids, medium-chain fatty acids and cytokines without significant loss of albumin from the circulation. Some examples of commonly available artificial liver support systems are the Molecular Adsorbent Recirculating System (MARS®; Gambro, Stockholm, Sweden) and Hepa Wash® (Hepa Wash GmbH, Munich, Germany). Biological liver support uses whole animal or human liver, and the liver support–detoxification is achieved by portal and/ or artery perfusion. Some examples of commonly available biological liver support systems are the Extracorporeal Liver Assist Device (ELAD®; Vital Therapies Inc., San Diego, CA, USA) and the HepatAssist® system (Alliqua Inc., Langhorne, PA, USA).

Bioengineering of liver for transplantation

The shortage of donor organs combined with ever-increasing liver disease has directed attention towards growing implantable liver tissue in the laboratory setting. Recent developments in decellularisation (removing cells from the tissues) and recellularisation (growing cells within the tissue) techniques have opened up exciting avenues for liver whole-organ reengineering. In an aim to replicate the liver extracellular matrix, two- and three-dimensional biodegradable artificial scaffolds have been fabricated using polymer compounds, which can host liver cells and function as a dialysis machine for the liver. Recent progress in decellularisation and recellularisation of animal liver has enabled the production of functional liver, albeit short-lived, and has the potential to develop further. Porcine organs seem the most suitable alternative for scaffolds because their size is comparable to that of the human liver and there is also a lower risk of transmission of zoonoses with porcine liver than with other animals. Semi-xenotransplantation is another concept whereby porcine-derived scaffold is recellularised with human-derived hepatocytes to reduce the risk of hyperacute rejection, which is common with animal-derived whole organs. More work needs to be done to have a fully laboratory-grown liver that is suitable for clinical transplantation.

Hepatocyte transplantation

Hepatocyte transplantation has been suggested as a potential alternative to orthotopic LT for several liver diseases and as bridging therapy in cases of liver failure. The clinical success of hepatocyte transplantation has been in the group of liver diseases that are characterised by the absence or reduced levels of enzymes, such as congenital hyperbilirubinaemia (Crigler–Najjar syndrome) due to uridine diphosphate glucuronosyltransferase-1 (UGT1) enzyme deficiency, familial hypercholesterolaemia due to low-density lipoprotein receptor (LDLR) deficiency, factor VIII deficiency, glycogen storage disease type I and ornithine transcarbamylase (OTC) deficiency, or in patients with urea cycle defects. The total number of cells transplanted usually ranges from 5% to 10% of the theoretical liver mass. However, it was found that the effect decreased over time and patients ultimately need whole-liver transplantation because of the failure of the hepatocyte graft. Despite efforts to isolate hepatocytes and their experimental transplantation since 1940, the clinical outcomes with hepatocyte transplantation have not been as good as expected because of the lack of efficacy, the limited availability of donor livers, difficulty in isolating good-quality liver cells, difficulty in cryopreservation of hepatocytes, minimal engraftment efficiency, poor proliferation and early rejection. This therapy would need repeated hepatocyte infusions, which currently is limited by the shortage of adequate donor organs.