Chapter 97A Liver transplantation
Indications and general considerations
Overview
It is difficult to identify any one cause for the increase in success. The contribution of better surgical and anesthetic techniques, improved postoperative care, and availability of better immunosuppressive agents have all contributed to the improvements in survival (see Chapter 97B). In addition, understanding of both indications and contraindications for the procedure have improved such that major surgery is not carried out in patients with virtually no chance of surviving, and patients are referred for transplantation at a stage when they are likely to have the greatest chance of success.
General Indications
Absolute Contraindications to Transplantation
• The patient is not fit enough to withstand surgery, for example, because of advanced cardiac or pulmonary disease.
• The patient is unlikely to survive the procedure, such as with active sepsis.
• Survival after transplantation may be too short to justify the risks of transplantation, as in the case of metastatic disease.
• Active alcoholism and substance misuse is present, evident by noncompliance with medical advice ascertained on psychiatrist or psychologist evaluation.
• The postoperative quality of life may be unacceptable to the patient, for example, as with severe, intractable depression.
• Surgery is technically impossible, as in patients with extensive venous thromboses.
Relative Contraindications to Transplantation
• Age may be an issue, and age restrictions vary at transplant centers; biologic age, rather than chronologic, is more important.
• Cholangiocarcinoma is sometimes a contraindication; transplant may still be considered, but only in highly selected patients because of the high risk of early recurrence.
• Chronic or refractory infections may preclude transplantation, depending on the nature of the infection and whether it is amenable to cure with available therapy.
• Poor social support may be a contraindication, particularly in biologically older patients with prolonged recovery anticipated after transplantation.
General Aspects
Nutrition
Malnutrition is a common finding in end-stage cirrhosis, with a prevalence of 81% (Caregaro et al, 1996). Malnutrition in these patients has many causes: the disease depletes the patient, and the situation is compounded by poor intake, malabsorption, and dietary restrictions that are often inappropriate. Malnutrition is associated with increased susceptibility to infection and poor healing. Although in liver disease, the degree of malnutrition may be difficult to quantify, malnourished patients fare poorly, with reported mortality of 15% (Campillo et al, 2003). Although no convincing evidence proves that improvement in nutrition alters the outcome, it seems prudent to optimize nutrition (Figueiredo et al, 2000), and it is sensible to correct vitamin and other nutrition deficiencies.
Psychologic Assessment
Transplantation is associated with major psychologic stress, both for the patient and the family. More than half of those in the liver transplant candidate population have a wide range of psychologic health problems (Day et al, 2009). Initially, many centers arranged for full psychologic and psychiatric assessment of all potential transplant candidates, but this is rarely undertaken. Chronic ill health, possible subclinical encephalopathy, and future uncertainties all combine to make it difficult to accurately predict a patient’s outcome. In addition, when a history of psychiatric illness is present, expert assessment is required. Some patients with psychiatric illness that is unresponsive to therapy and those with a history of recurrent episodes of self-harm may not be suitable candidates for transplantation.
Age
There is no agreed upper age limit, but advanced age is associated independently with mortality after transplant (Burroughs et al, 2006). The concept of biologic age has superseded that of chronologic age, although the former cannot readily be defined or quantified.
Previous Abdominal Surgery
The presence of adhesions, especially in the presence of portal hypertension, adds considerably to the difficulties of surgery and may affect outcome, especially when this involves surgery to the biliary tree (Neuberger et al, 1999).
Infection
Human Immunodeficiency Virus
Although early studies showed patients with HIV infection fared poorly (Rubin et al, 1987; Tzakis et al, 1990), with the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has been greatly altered (Roland & Stock, 2006), although patients with hepatitis C virus (HCV) coinfection are at high risk for developing end-stage liver disease (Graham et al, 2001). Short-term outcomes in patients with HIV are encouraging (Fung et al, 2004), but the procedure remains limited to a few centers. Indications are becoming better defined (Samuel et al, 2003) and include 1) end-stage liver disease, 2) low or undetectable levels of HIV RNA, 3) no autoimmune deficiency syndrome (AIDS)-defining complication, and 4) a CD4 count greater than 200/mL.
Cardiovascular Disease
As with other diseases, the prognosis of patients with cardiovascular diseases will dictate whether liver replacement is an appropriate therapy. Multivessel, moderate to severe coronary artery disease is present in 15% of patients with end-stage liver disease (Tiukinhoy-Laing et al, 2006). Preoperative assessment of cardiovascular status is, at best, imprecise, as no clear guidelines exist to define limits below which grafting is unsafe. When it is possible to correct coronary artery disease, this should be undertaken prior to transplantation.
Respiratory Function
Arterial hypoxemia, an oxygen saturation less than 92% or arterial oxygen pressure less than 70 mm Hg, may be found in up to 70% of patients with liver disease. Several possible causes for this hypoxemia include ventilation-perfusion mismatch, diffusion limitation, alveolar hypoventilation, shunt, and diffusion-perfusion abnormality (Krowka & Cortese, 1990). Furthermore, pulmonary dysfunction is present in up to 2% of patients with advanced liver disease. The presence of significant pulmonary disease is usually apparent on history and examination, but significant pulmonary disease may be cryptic. The many possible causes for these abnormalities include 1) diseases unrelated to the liver, such as those caused by smoking; 2) organic liver disease, such as α1-antitrypsin deficiency; 3) respiratory conditions associated with certain liver disease, such as fibrosing alveolitis associated with primary biliary cirrhosis; 4) the effects of the liver disease on respiratory function, such as ascites that causes a pleural effusion or simple lung compression; 5) hepatopulmonary syndrome, and 6) portopulmonary hypertension.
Hepatopulmonary Syndrome
Hepatopulmonary syndrome is characterized by abnormal intrapulmonary vascular dilation (Hoeper et al, 2004). Clinically, it encompasses a triad of arterial deoxygenation, intrapulmonary vascular dilation, and liver disorder. The diagnosis is suggested by showing orthodeoxia, a fall in arterial blood oxygen when standing, and the presence of intrapulmonary shunting, demonstrated by either bubble echocardiography or nuclear medicine scanning.
Portopulmonary Hypertension
Portopulmonary hypertension results from pulmonary vasoconstriction and leads to vascular remodeling, which results in pulmonary hypertension (Hoeper et al, 2004). Diagnostic criteria include presence of liver disease that results in portal hypertension; mean pulmonary arterial pressure of more than 25 mm Hg at rest or 30 mm Hg during exercise; mean pulmonary artery occlusion pressure of less than 15 mm Hg; and pulmonary vascular resistance more than 240 dyn/sec/cm−5 (Krowka, 2003).
No clear guidelines are available that establish when liver transplantation is contraindicated because of pulmonary disease (Krowka et al, 2004). A preoperative partial pressure of oxygen of less than 50 mm Hg and a lung scan with brain uptake of more than 20% (Arguedas et al, 2003) strongly predict mortality, although these patients may be candidates for a triple transplant of heart, lung, and liver. Similar considerations apply to those with cystic fibrosis, cystic lung disease, and liver disease. Long-term oxygen therapy is the most frequently recommended therapy for symptomatic hypoxemic patients, but the use of drugs and transjugular intrahepatic shunt (TIPS) requires validation in this setting.
Coexisting Disease
The presence of coexisting disease may affect the decision to offer the patient a liver graft, either because the prospects of recovery are adversely affected, or because long-term survival may be reduced (Volk et al, 2007). Diabetes mellitus (DM) is commonly found in patients with chronic liver disease, especially in those with HCV infection. DM may occur as a consequence of the insulin intolerance associated with advanced liver disease; if so, it will resolve after successful transplantation. Concerns for those with diabetes center upon the possible microvascular complications. Evidence of a proliferative retinopathy, diabetic nephropathy, or autonomic neuropathy—evidenced by simple tests, such as abnormal beat-to-beat variation on Valsalva maneuver or postural hypotension—may be relative contraindications for transplantation. The presence of advanced microvascular disease puts the patient at risk of major autonomic disruption during the procedure, and the survival of such patients is relatively poor (Haydon & Neuberger, 2001).
Hyponatremia is a common finding in patients with advanced chronic liver disease, and it usually occurs either as a consequence of injudicious diuretic therapy or because of the reduced free-water clearance. Grafting patients with severe hyponatremia (serum sodium <120 mmol/L) has shown an increased risk of central pontine myelinolysis (Yun et al, 2009). Significant hyponatremia should be corrected prior to transplantation, either by simple water restriction and, if appropriate, cessation of diuretic therapy or, if more rapid correction is required, by use of renal support (Elias & McMaster, 1987). The role of aquaretics may also be helpful in this situation (O’Leary & Davis, 2009).
Renal disease may occur either as a consequence of the hepatorenal syndrome or as a result of intrinsic kidney damage. In the hepatorenal syndrome, the kidney is not structurally damaged, and once good liver function is reestablished, the kidney will function normally; so although the prognosis may be poorer in the presence of advanced renal insufficiency (Rimola et al, 1987), the hepatorenal syndrome is not an absolute contraindication to transplantation. When coexisting advanced renal disease is evident, it may be advisable to consider combined liver and kidney transplantation, as renal function remains a major predictive factor for the outcome after transplantation (Nair et al, 2002). It is uncertain whether pretransplant correction of renal parameters—for example, by dialysis—is associated with an improvement in survival.
Past history of malignancy is a relative contraindication to transplantation, because the effect of surgery and the consequent immunosuppression may predispose the patient to early recurrence of tumor (Penn, 1993; Saigal et al, 2001). In 1993, Penn identified those tumors that have a high risk of recurrence after transplantation (Box 97A.1). Most centers will offer transplantation when the risk of recurrence is below 10% at 5 years; however, recurrence rates with other kinds of malignancies—colorectal cancer (18.8%), nonmelanoma skin cancers (23.5%), thyroid carcinoma (25%), oral squamous carcionoma (33%), vulvovaginal cancers (33%), and breast carcinoma (33%)—are associated with a higher risk following liver transplantion (Benten et al, 2008). In only exceptional cases should patients with any of the above extrahepatic malignancies be considered suitable candidates for transplantation.
Box 97A.1
Effect of Immunosuppression on Tumor Recurrence
From Penn I, 1993: The effect of immunosuppression on pre-existing cancers. Transplantation 55:742-747.
Bone Disease
Many patients with chronic liver disease will have bone disease. The occurrence of osteomalacia as a consequence of vitamin D malabsorption is low and can readily be corrected by parenteral administration of vitamin D; however, osteoporosis is a far greater problem and is particularly seen in female patients with chronic cholestatic disease. In many cases, successful transplantation will halt or retard the progression and may even improve bone mineralization (Guichelaar et al, 2007). The presence of severe osteoporosis may result in additional complications in the presence of significant thoracic or lumbar vertebral collapse or fractures. The development of severe osteoporosis may well be an indication for transplantation in itself.
Specific Diseases
Fulminant Hepatic Failure (See Chapter 97C)
In recent years it has been realized that liver transplantation is an effective form of therapy for patients with fulminant hepatic failure (FHF), that is, the presence of encephalopathy occurring within 8 weeks of the onset of symptoms in a patient with previously normal liver (Peleman et al, 1987; Chapter 97C). FHF requiring transplantation accounts for less than 5% of liver transplantations. In those with severe FHF and grade 4 hepatic encephalopathy, the mortality approaches 80%. Common causes of FHF include paracetamol (acetaminophen) overdose; viral infections, such as hepatitis A, B, E, and rarely C; drug and xenobiotic toxicity, including those caused by herbal remedies; Wilson disease; and liver diseases of pregnancy.
Patients with FHF develop early multiorgan failure and require intensive supportive therapy. The common causes of death are cerebral edema, multiorgan failure, sepsis (bacterial or fungal), cardiac arrhythmia or arrest, and respiratory failure (Ostapowicz et al, 2002). Indeed, FHF poses a difficult problem, because the window is very narrow between the time when it is apparent that the patient’s survival is likely to be poor in the absence of transplantation and the onset of irreversible complications that preclude a successful outcome.
Several groups have now published prognostic factors, and based on those, criteria for super-urgent transplantation in the United Kingdom have been published; these are listed in Table 97A.1 (Bismuth et al, 1987; Neuberger et al, 2008; O’Grady et al, 1989). The King’s College model has been validated in other centers and was found to be robust, although it is likely that with advances in the medical management of patients with FHF, these prognostic factors will require modification. The inclusion of serum lactate in the King’s College prognostic criteria provides greater accuracy (Riordan & Williams, 2002).
Table 97A.1 Current Transplant Criteria in the United Kingdom for Registration as a Super-Urgent Transplantation for Fulminant Hepatic Failure
| Category | Etiology |
|---|---|
| 1 | Acetaminophen poisoning with pH <7.25 >24 h after overdose and after fluid resuscitation |
| 2 | Acetaminophen poisoning with PT >100 sec, or INR >6.5 and serum creatinine >300 mmol/L, or anuria and grade 3 to 4 encephalopathy |
| 3 | Acetaminophen poisoning with serum lactate level >24 h after overdose >3.5 mmol/L on admission or >3.0 mmol/L after fluid resuscitation |
| 4 | Acetaminophen poisoning with 2 of the 3 criteria from category 2 with clinical evidence of deterioration (e.g., increased ICP, Fio2 >50%, increasing inotrope requirements) in the absence of clinical sepsis |
| 5 | Seronegative hepatitis, hepatitis A, hepatitis B, or an idiosyncratic drug reaction with PT >100 sec or INR >6.5 and any grade of encephalopathy |
| 6 | Seronegative hepatitis, hepatitis A, hepatitis B, or an idiosyncratic drug reaction; any grade of encephalopathy; and any three from the following: unfavorable etiology (idiosyncratic drug reaction, seronegative hepatitis), age >40 years, jaundice to encephalopathy time >7 days, serum bilirubin >300 mmol/L, PT >50 sec or INR >3.5 |
| 7 | Acute presentation of Wilson disease or Budd-Chiari syndrome, a combination of coagulopathy, and any grade of encephalopathy |
| 8 | Hepatic artery thrombosis on days 0 to 21 after liver transplantation |
| 9 | Early graft dysfunction on days 0 to 7 after liver transplantation with at least two of the following: AST >10,000 IU/L, INR >3.0, serum lactate >3 mmol/L, absence of bile production |
| 10 | Severe liver failure in any liver donor within 4 weeks of a donor operation |
AST, aspartate aminotransferase; Fio2, inspired oxygen concentration; ICP, intracranial pressure; INR, international normalized ratio; PT, prothrombin time
Modified from Neuberger et al, 2008: Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut 57(2):252-257.
One of the best guides to progression is given by serial estimation of the prothrombin time (Harrison et al, 1990) or factor V levels (Bernuau et al, 1986), because in the absence of extraneous blood products, these best represent the synthetic function of the liver. Initial improvement in the prothrombin time followed by deterioration suggests the presence of sepsis; therefore such patients should no longer be considered potential candidates. In addition, the patient remains at risk of developing complications related to raised ICP for up to 48 hours after successful transplantation (Dabos et al, 2004; Keays et al, 1991).
Because many of the extrahepatic manifestations of FHF may be a consequence of the presence of large amounts of necrotic tissue, some centers have advocated the use of a two-stage procedure, whereby the failed liver is removed, and the patient remains anhepatic until a suitable graft can become available (Ringe et al, 1993). Although there is little doubt that following hepatectomy, the patient’s condition may well improve, few convincing data are available at present to suggest that this approach improves outcome; however, such a procedure may be indicated in a patient who is rapidly deteriorating for whom a graft has been found, but logistic conditions may enforce some delay before the graft can be successfully performed.
One of the dilemmas in considering liver transplantation in patients with acute liver failure is that if the liver does recover, a complete return to normal structure and function is likely. The use of auxiliary transplantations, such as auxiliary partial orthotopic liver transplantation, or partial transplantations may allow the earlier use of liver grafting as a safety net; because if the patient’s liver does recover, the donor liver can be removed or allowed to atrophy, and the patient can return to a life of good liver function free of immunosuppression. The use of artificial liver support devices (Chapter 72) remains uncertain, but systems such as the molecular absorbent recirculation system (MARS; Gambro AB, Sweden) may offer a bridge to transplantation (Mitzner et al, 2002).
Metabolic Diseases
A number of metabolic diseases account for less than 5% of liver transplantations in adults, and these may be corrected by liver transplantation (Table 97A.2). In some cases, where the metabolic defect arises in the liver, transplantation will correct that defect. This is seen, for example, with Wilson disease or hemophilia. In other conditions, such as some types of hypercholesterolemia, the metabolic defect occurs within the liver, but the heart is the organ affected. Some centers have advocated the use of liver transplantation to prevent the onset of severe coronary artery disease, although when cardiac disease is already present, combined heart and liver transplantations may also be performed. Similar considerations apply to hyperoxaluria that requires liver and kidney replacement. In other conditions, such as hemophilia, with alternative therapies such as replacement with factor VIII, transplantation should only be considered if liver disease is extensive, such as may occur with HCV infection transmitted via blood products.
Table 97A.2 Inborn Errors of Metabolism that Have Been Treated by Liver Transplantation
| Liver Affected | Other Organs Also Affected |
| α1-Antitrypsin deficiency | Primary hyperoxaluria |
| Wilson disease | Crigler-Najjar syndrome |
| Protoporphyria | Primary hypercholesterolemia |
| Tyrosinosis | Niemann-Pick disease |
| Tyrosinemia | Sea-blue histiocyte disease* |
| Galactosemia |
