Liver Transplantation

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197 Liver Transplantation

Orthotopic liver transplantation (OLTX) is the definitive treatment for patients with end-stage liver disease (ESLD). It affords the opportunity for a disabled person to return to a full and active life. Although expensive, OLTX may well be more cost-effective than the routine medical care of terminally ill patients with liver failure.1,2 The first OLTX in humans was performed by Starzl in 1963.3 However, significant progress did not occur until the advent of potent immunosuppressive agents, specifically the introduction of cyclosporine in 1981.4 Technical improvements in surgical approach and organ preservation, combined with increasingly sophisticated anesthetic and intensive care management, have provided 1-year survival rates of nearly 90%.

In this chapter, we outline the many developments that have occurred in this field. Major advances in defining risk categories for candidates and managing patients with cirrhosis and pulmonary hypertension and novel immunosuppressive strategies are described. In recent years, organ allocation has been prioritized such that the sickest patients, those most likely to die, undergo transplants first. This optimizes both aggregate benefit, by improving overall survival of patients with end-stage liver disease, and individual benefit. The latter is manifested by the full recovery of a very sick patient. Conversely, the individual who is not so ill will not bear the risks of surgery. Since February 2002, all patients listed in the United States for liver transplantation have been prioritized by their score on the Model for End-Stage Liver Disease (MELD).5,6

image Candidate Selection

Optimal candidates are those for whom the risk of surgery is far outweighed by the potential improvement in their quality of life. Furthermore, the risk of recurrence of the primary disease should be low.7,8 Not surprisingly, those who are at the highest risk with surgery also achieve the greatest gains when they survive. Unfortunately, such patients have a higher mortality and require significantly greater resources, particularly intensive care and rehabilitation. There are few absolute contraindications to OLTX. However, factors have been identified that significantly increase the risk and should be recognized as relative contraindications (Table 197-1). From the surgical perspective, prior right upper quadrant abdominal surgery, particularly biliary reconstruction, results in a technically more difficult procedure. Patients who are sicker with higher MELD scores or U.S. United Network Organ Sharing (UNOS) Status,1,9 particularly those with fulminant hepatic failure, fare worse. Patients with higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores who are in the intensive care unit (ICU) and require mechanical ventilation or hemodialysis have lower survival. Of course, medical therapy in such circumstances is even less successful, and APACHE II models hospital outcome well. However, after transplantation, mortality does not rise linearly as a function of recipient acuity. Patients with high APACHE II scores have a higher post-OLTX mortality than recipients with very low preoperative scores. However, there is a plateau of approximately 25% for recipients with preoperative APACHE II scores greater than 20 (Figure 197-1). This observation suggests that carefully selected but very ill patients benefit from OLTX.

TABLE 197-1 Contraindications to Liver Transplantation

Absolute Relative
Extrahepatic malignancy Cholangiocarcinoma, hepatocellular carcinoma larger than UCSF modification of Milan criteria (see text)
AIDS
Hepatitis B with active replication
HIV infection (in the absence of AIDS)
Low cerebral perfusion pressure (sustained < 40 mm Hg or cerebral blood flow < 10 mL/min/100 g) in fulminant hepatic failure
Infection (extrahepatic)
Low cerebral perfusion pressure (sustained < 60 mm Hg or cerebral blood flow < 20 mL/min/100 g) in fulminant hepatic failure
Portal vein and superior mesenteric vein thrombosis
Extrahepatic organ system failure not related to the ESLD
Pulmonary hypertension (mPAP > 45 mm Hg or depressed RV function) Pulmonary hypertension (25 < mPAP < 45, preserved RV function at rest and with exercise)
Hepatopulmonary syndrome (PaO2 < 100 mm Hg with FIO2 = 100%) Hepatopulmonary syndrome (PaO2 < 200 mm Hg with FIO2 = 100%)

AIDS, acquired immunodeficiency syndrome; ESLD, end-stage liver disease; HIV, human immunodeficiency virus; mPAP, mean pulmonary artery pressure; RV, right ventricular.

Patients with cirrhosis and underlying hepatocellular carcinoma are candidates for OLTX if the disease is limited to the liver and the lesions are small, there is no evidence for major intrahepatic venous invasion, and nodal disease is absent. The widely accepted Milan criteria (1 lesion less than 5 cm or 3 lesions each less than 3 cm) have been modified and established as the University of California at San Francisco (UCSF) criteria (1 lesion = 6.5 cm or 3 or fewer nodules with the largest = 4.5 cm and the total tumor diameter = 8 cm without gross vascular invasion); survival is more than 80% for these patients.10 Extensive radiologic staging of these patients to stratify them into tumor stages is imperative so the risk of postoperative recurrence can be estimated. Patients with biliary tract malignancy such as cholangiocarcinoma have a very high rate of recurrence.11,12 It seems doubtful that more extensive resection, including the liver, a portion of small bowel, and pancreas, will be more successful in controlling recurrence of these tumors.13,14 Preoperative chemotherapy and irradiation may improve outcome after liver transplantation and is under investigation.15

The risk for recurrence of viral hepatitis in the transplanted organ differs for hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), and hepatitis E. HAV is an acute illness that may cause fulminant hepatic failure and does not recur after transplantation. Recurrence of HBV, once a near-universal problem16 except after transplantation for fulminant HBV, has been greatly reduced by the routine use of hepatitis B immune globulin (HBIG) titrated to levels of anti-HBV surface antigen antibody (HbsAb) and antivirals such as tenofovir and entecavir—associated with less emergence of drug resistance than lamivudine and adefovir.17 Active HBV replication, documented by the presence of HBV-DNA, must be suppressed with antivirals before surgery.1824 For reasons that are unclear, early reports indicated that patients transplanted with HBV fared worse at each postoperative stage than those with other causes of ESLD.25 Some have speculated that this is a systemic disease accounting for both the high rate of reinfection in the absence of prophylaxis and the decreased survival. Hepatitis C presents a more complicated conundrum. Reinfection of the transplanted organ is universal. Currently there is no effective prophylaxis. Clinical progression is highly variable and not predictable. Some patients experience rapid deterioration and graft failure within the first year, but others have little histologic damage several years after liver transplantation. Hepatitis after transplantation may be treated with pegylated recombinant interferon (IFN)-α2b, and ribavirin, but is variably tolerated. Sustained suppression of HCV at the end of therapy is reported to be approximately 26% at 3 years.25 The effect of targeted immunosuppression, particularly reduced corticosteroid dosage, on recurrence of HCV and progression to fibrosis is under investigation.26

HIV-infected liver transplant recipients tolerate carefully titrated immuno-suppression. Survival after OLTX is only slightly lower for HIV-positive patients than it is for HIV-negative patients,9,2729 with post-transplant morbidity and mortality related to recurrence of hepatitis C in co-infected patients.30

Patients with thrombosed portal veins present a formidable surgical challenge. Options include portal endovenectomy or anastomosis of the donor portal vein to the confluence of the superior mesenteric and splenic veins. Patency of the superior mesenteric vein should be demonstrated by ultrasonography or magnetic resonance imaging (MRI) or angiography before surgery. Occlusion of the superior mesenteric vein usually precludes OLT. Although the portal vein may be anastomosed to the recipient inferior vena cava with a proximal caval ligature placed to sustain flow, mesenteric venous hypertension persists, and gastrointestinal (GI) hemorrhage, ascites, and lower-extremity edema remain problematic. Combined hepatic and intestinal transplantation or multivisceral transplantation are alternatives.31

Acute liver failure (ALF; known formerly as fulminant hepatic failure [FHF]) is liver failure with encephalopathy that develops in patients without prior liver disease within an 8-week period or less.32 Mortality is high and predictable.33 Liver transplantation is the only therapeutic option for patients with progressive liver failure, increasing survival at one year from 20% to 75%.34,35 Such patients are critically ill at the time of transplantation. They require intensive hemodynamic and neurologic monitoring preoperatively, including measurement of intracranial pressure (ICP)3640 and cerebral blood flow (CBF). A few patients will improve with supportive care, particularly young patients with acetaminophen intoxication, Amanita poisoning, or hepatitis A. But most experience a deterioration in their conditions. In contrast to patients with chronic liver disease, hepatic encephalopathy is associated with intracranial hypertension, particularly in patients with multiple organ system failure and hyponatremia.17,4145 Inadequate cerebral perfusion, cerebral herniation, and brain death preclude OLT.46 Progressive arterial vasodilation may result from the failing liver, mesenteric hypertension, infection, pancreatitis, and adrenal insufficiency, with resultant hypotension despite elevated cardiac output. Cardiovascular instability,47 atrial and ventricular arrhythmias,48 and respiratory insufficiency (acute lung injury/acute respiratory distress syndrome [ALI/ARDS]) are common complications of ALF and substantially increase operative risk. If preoperative support requires greater than 1 µg/kg/min of epinephrine (or equivalent) or positive end-expiratory pressure (PEEP) greater than 12 with FIO2 above 60%.

Patients with ESLD severe enough to make them eligible for OLT often experience a precipitous deterioration (acute on chronic liver failure, AoCLF) and require admission to the ICU. Common precipitants include infection (particularly pneumonia and spontaneous bacterial peritonitis) and GI bleeding (from esophageal or gastric varices, portal hypertensive gastropathy, or gastric or duodenal ulceration). Although these events herald the impending demise of the patient and intensify the search for a donor organ, they also further compromise the potential recipient and may lead to multiple organ dysfunction syndrome (MODS) and death.

The decision regarding when a patient is “too sick” to undergo OLTX is complex and reflects a balance of recipient acuity (assessed by MELD, APACHE, level of vasopressor, dialytic and ventilatory support), donor risk index, and surgical, anesthesia, and critical care resources available at the time the donor is identified. Comorbidity in the form of extrahepatic disease unrelated to liver failure with estimated 5-year mortality in excess of 50%, extrahepatic malignancy or infection, irreversible neurologic injury, and cardiopulmonary support in excess of that noted above for ALF would preclude OLT in our institution. Liver failure–associated MSOF resolves with restoration of liver function after successful transplantation.

image Donor Selection and Operation

Liver allograft function reflects both recipient and donor factors. Although individual donor characteristics such as age, steatosis, hypernatremia, and impaired lidocaine clearance49,50 have been associated with poor allograft function, a recent study of a large group of patients allowed analysis of donor factors while controlling for recipient-specific characteristics.51 Deceased donor characteristics which independently predicted an increased risk of graft failure included age, donation after cardiac death (DCD), split or partial grafts, race, height, and cause of death (Table 197-2). Decreased graft survival may also be associated with unique pairings of donor and recipient characteristics. For example, liver function in HCV-positive recipients is worse when the donor is older than 60 years of age.52

Brain death results in marked changes in homeostasis for the donor. Hemodynamic instability is common and may result in part from massive free-water deficits caused by diabetes insipidus. Correction of diabetes insipidus with desmopressin and adequate hemodynamic monitoring and intervention are essential to preserve vital organ function. Anesthesia blunts the response to surgical stimulation. A skilled surgical dissection with rapid identification of the hepatic vessels,53 cannulation and perfusion with University of Wisconsin (UW) solution, and rapid cooling are essential for graft preservation. Acceptable cold ischemia times have dropped. Despite a report of successful graft function after prolonged cold ischemia times of up to 24 hours,54 the best outcome is associated with 6 hours or less.

Donation after cardiac death (DCD) results in a graft with an additional warm ischemic insult–a consequence of the hypotension and hypoxemia of that result from with drawal of hemodynamic and respiratory support–until death is pronounced and cannulae can be placed to infuse cold preservative solution. Alternative preservation techniques including less viscid than cold UW solution as well as allograft perfusion with thrombolytics are under investigation.55 A significant learning curve attends the successful use of DCD grafts with biliary complications noted by all but lower survival and hepatic arterial thrombosis reported by some56 but not all programs.57

Living donation is the only option for liver transplantation in many parts of the world. However, in the United States the number of living donor liver transplants is falling from its peak in 2001—constrained by the success of deceased donor liver transplantation, including the falling overall mortality after introduction of MELD for liver allocation and the risks inherent in the donor surgery. In 2009 only 219 liver transplants were from living donors, compared with 6101 from deceased donors.58 Evaluation includes confirmation of the emotional relationship between donor and recipient, evaluation of the donor for medical disease, and anatomic compatibility. Liver segment to donor weight ratios of 0.8% to 1% are needed to avoid small-for-size syndrome. However, donation of the right lobe results in increased donor complications. The reader is referred to a recent detailed review.59

image Recipient Operation

The recipient operation has become a highly refined surgical procedure. Improvements in anesthetic and surgical practice have made evident the importance of the other factors described previously—candidate selection and donor organ quality—in the eventual outcome for the recipient. The surgical procedure may be divided into three stages: hepatectomy, anhepatic phase, and post-reperfusion phase. Each involves special consideration by the anesthesiologist and surgeon.

Monitoring includes pulse oximetry, electrocardiography, and continuous measurement of arterial pressure (often from two vessels) and pulmonary arterial pressure. Maintenance of large-bore central venous catheters (e.g., two 8.5F introducers) and the ability to infuse whole blood at rates as high as 2 L/min with a rapid infusion system are essential to maintain hemodynamic stability during occasional episodes of massive hemorrhage. More extensive monitoring is indicated in selected cases. Right ventricular function may be compromised by the presence of pulmonary hypertension, a complication that can develop acutely during reperfusion.6063 Right ventricular ejection fraction and end-diastolic volume are more sensitive guides to cardiac preload than are central venous and pulmonary artery occlusion pressures. These values may be obtained by use of the oximetric pulmonary artery with rapid-response thermistor catheter (Edwards Lifesciences Corp., Irvine, California).1 However, more robust cardiovascular assessment is provided by intraoperative transesophageal echocardiography. This tool provides a dynamic online picture to the anesthesiologist, allowing him or her to assess the adequacy of resuscitation. In patients with ALF and intracranial hypertension, ICP monitoring is essential. Although CBF measurement in the operating room is difficult, flow can be estimated by the contour of the transcranial Doppler and balance of oxygen supply and demand inferred from the arterial-jugular venous oxygen content difference.64 CBF also may be assessed using transcranial Doppler ultrasound to measure the velocity of flow in the middle cerebral artery. Continuous electroencephalography (EEG) and compressed spectral array are under investigation as monitoring techniques in this setting.

A rapid-sequence induction of anesthesia is indicated, as gastric motility is impaired in patients with cirrhosis, and the procedure may be performed before an adequate period of fasting. Anesthesia is often induced with propofol, fentanyl and succinylcholine and maintained with a balanced technique of volatile anesthetics (isoflurane), muscle relaxation (cisatracurium, vecuronium), and judicious use of narcotics (fentanyl) and benzodiazepines (midazolam).65

Monitoring of the coagulation capacity of the recipient is complicated because clotting is usually markedly deranged, and it is necessary to rapidly correct problems. Depletion of coagulation factors and thrombocytopenia are common. Primary fibrinolysis may be evident early in the procedure but does not require treatment in the absence of significant bleeding, which may become problematic during the anhepatic phase. Standard measures of coagulation—prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count—are very sensitive. However, attempts to correct these values result in excessive transfusion of blood products. There is often significant delay between the time blood is sampled and the results from clotting assays are reported. Finally, standard measures of coagulation provide little timely information about qualitative platelet function and fibrinolysis. Kang and colleagues introduced the thromboelastograph for routine use during OLT.66 This test provides the anesthesiologist with a rapid assessment of coagulation status, the presence or absence of fibrinolysis, and the effects of intervention with protamine or ε-aminocaproic acid, an inhibitor of fibrinolysis.6668

The surgical procedure involves meticulous dissection, which is often hampered by severe portal hypertension and substantial bleeding from venous collaterals. Insufficient control results in significant blood loss. Identification of the hilar structures may be complicated by adhesions from prior biliary tract surgery. Patency of recipient vessels and adequacy of blood flow must be assessed before placing the graft into the surgical field. An arterial graft for the hepatic artery may be chosen when the recipient anatomy is anomalous or the caliber of the vessels is too small, or when atherosclerosis narrows the celiac trunk. Other indications for an arterial graft include a marked size discrepancy between the recipient and donor vessels and inadequate length of the donor artery. Portal venous thrombosis may be managed with a “jump” graft from the superior mesenteric vein if the portal vein cannot be thrombectomized.69 The donor and recipient caval veins are usually anastomosed end-to-end caudad and cephalad to the liver when a cava-sparing technique is not chosen.

Preservation of blood flow in the inferior vena cava (caval preservation) with or without portal drainage is an alternative technique, also known as a piggyback7072 and is preferred when there is marked hemodynamic instability. Venovenous bypass was used routinely in the past because it afforded greater hemodynamic stability and reduced mesenteric congestion (Figure 197-2).73 However, the piggyback approach requires one less anastomosis and no dissection of the groin or axilla, decreasing the time for surgery by 1 hour. The biliary anastomosis is fashioned after the vascular anastomoses are completed and the graft reperfused. Two options are used: choledochocholedochostomy or mid-jejunal Roux-en-Y limb with choledochojejunostomy. The former procedure requires less dissection and is restorative. Unfortunately, the stenosis rate is quite high. Diseases which involve the extrahepatic bile ducts, such as sclerosing cholangitis, require resection of the bile duct and creation of a choledochojejunostomy. Stenting of the biliary anastomosis—once routine with a T tube—is now controversial. One innovative approach is cannulation of the donor cystic duct after donor cholecystectomy with a 5F catheter which stents the anastomosis, drains some bile for daily inspection and provides a noninvasive route for cholangiography. A hemorrhoidal band serves to seal the cystic duct once the drain is removed.

image

Figure 197-2 Venovenous bypass. I.V.C, inferior vena cava; ext. iliac v., external iliac vein.

(From Griffith BP, Shaw BW Jr, Hardesty RL, Iwatsuki S, Bahnson HT, Starzl TE. Veno-venous bypass without systemic anticoagulation for transplantation of the human liver. Surg Gynecol Obstet 1985;160:270-2, with permission.)

Reperfusion is accompanied by cardiovascular collapse in a small (and decreasing) number of patients (∼2%-5%).74 Although the exact mechanism is undefined, recirculation results in a cardiac bolus of cold acid and potassium-rich fluid, resulting in acidemia, hyperkalemia, and hypocalcemia. The consequence is abrupt onset of a severe, albeit brief, cardiomyopathy coincident with the loss of vasomotor tone and, occasionally, increased pulmonary arterial pressure. Volume resuscitation, sodium bicarbonate, or THAM for correction of metabolic acidosis, calcium chloride, and inotropic support (epinephrine) are usually sufficient to restore hemodynamic stability. Fortunately, this event is usually short lived. However, significant insults to the graft, heart, kidneys, and brain may occur and require postoperative attention.

image Postoperative Management

As might be surmised from the preceding discussion, postoperative management of the OLT recipient is largely governed by the patient’s preoperative condition, the adequacy of the donor organ, and the operative success of the surgical and anesthetic teams. Indeed, the function of the graft is the dominant factor in the recovery of the patient.

Liver Allograft Function

Early graft function is usually assessed by measuring circulating concentrations of total bilirubin, aminotransferases, canalicular enzymes, and clotting factors. The scheme shown in Table 197-3 is useful for assessing graft function according to these parameters.75 Other parameters such as arterial ketone body ratio (AKBR)76 and oxygen consumption77 also correlate with graft survival. However, in a retrospective review, Doyle and colleagues were unable to identify a unique parameter with adequate sensitivity and specificity to be useful for predicting graft survival in individual OLTX recipients.78 Other techniques, such as neural network modeling, require further investigation.79 An alternative approach is to use a composite acuity score to predict graft and patient survival. For example, Angus et al. showed that the APACHE II score, a widely used severity-of-illness indicator designed for general ICU patients, was useful for predicting both hospital survival and survival at 1 year for liver transplant recipients if the model was recalibrated.80,81

Typically, elevated serum bilirubin levels during the first few days after transplantation reflect preoperative values and the consequences of procurement. In the absence of severe procurement injury, serum total bilirubin concentration typically falls to normal during the first week. An injury pattern is evidenced by elevated serum aminotransferase levels. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) peak during the first 3 days and return toward normal slowly thereafter. Canalicular enzymes (γ-glutamyl transpeptidase and alkaline phosphatase) typically rise to four or five times normal and return toward normal over the course of the next few weeks. If the liver was injured during procurement, the biochemical changes are greater and last longer. Thus, the peak concentrations for ALT and AST are higher, and the serum total bilirubin concentration remains abnormal for a prolonged period, sometimes for weeks, as do circulating levels of canalicular enzymes. Unless the liver is irreversibly damaged, synthetic function normalizes after the third day, and the AKBR returns toward 1.0. Primary nonfunction is liver allograft failure manifested as jaundice, coagulopathy, and encephalopathy. It is not explained by technical or immunologic factors. Multiple-system organ failure may develop or worsen as liver function deteriorates. Re-transplantation may be the only option.

Knowledge of the details of procurement and implantation should color the interpretation of liver function abnormalities in the early postoperative period. Technical problems should always be considered before an immunologic mechanism is implicated. Even with the widespread use of percutaneous liver biopsy, a diagnosis based solely on histology may be inaccurate when a vascular or biliary drainage problem is present. Furthermore, if a technical problem is not recognized and is treated as rejection, intensified immunosuppression places the patient at grave risk for infectious complications.

The diagnostic work-up for a patient with liver function abnormalities in the perioperative period should include a Doppler ultrasound examination to determine patency of all pertinent vessels. Concern about the adequacy of flow should prompt an angiogram or MR angiogram (MRA). Early occlusion of the hepatic artery should prompt immediate re-exploration, which can result in a nearly 50% graft salvage rate.82 Early hepatic artery thrombosis may present as a precipitous deterioration in hemodynamics, abrupt development of ARDS, severe coagulopathy, and markedly elevated serum aminotransferase concentrations. Bacteremia is common. Delayed hepatic artery thrombosis is often less dramatic in its presentation.83 Indeed, some patients are asymptomatic. Others show destruction of the biliary duct system with multiple intrahepatic strictures, bile collections, and intrahepatic abscesses. Recurrent bacteremia, in the absence of another source, may be the only indication of hepatic artery thrombosis.

The presentation of portal venous thrombosis is usually much less dramatic. In the early postoperative period, the most frequent manifestation is persistent ascites. Enteric congestion and bleeding as a consequence of portal hypertension may also occur. Later, portal vein thrombosis should be considered in the differential diagnosis if the patient develops variceal hemorrhage. Although occlusion of the inferior vena cava (IVC) related to retrohepatic caval thrombosis can occur, it is uncommon. Anastomotic strictures are more common. Stenosis at the lower anastomosis of the IVC presents as lower-extremity edema and renal dysfunction. Stenosis at the upper anastomosis presents findings similar to those that occur in the Budd-Chiari syndrome, including passive congestion of the liver, ascites, lower-extremity edema, and renal failure. The diagnosis may be suggested by ultrasound examination, but more commonly the clinical picture prompts measurements of IVC pressures above and below the anastomoses using a fluoroscopically guided catheter. When strictures are diagnosed, treatment is commonly surgical, but balloon dilatation has been accomplished in some cases.

Patency of the biliary tract should be confirmed using cholangiography, which is simple when a T-tube or cystic duct tube stents the anastomosis. A more invasive approach is needed in patients without a biliary drainage tube: ERCP for a choledochocholedochostomy and percutaneous transhepatic cholangiography (PTC) for a choledochojejunostomy. Small anastomotic leaks may be managed with an internal stent. Larger leaks or uncontrolled peritonitis warrant surgical repair. Adequate hepatic arterial flow should be confirmed.

Graft rejection may occur at any point after OLT. Hyperacute rejection is very rare, if it occurs at all, after OLTX. Nevertheless, a humoral component of rejection may be evidenced by antibody deposition in the arterial endothelium and by persistence or recrudescence of a positive cross-match.84 Acute cellular rejection (ACR) is more common and develops in approximately 40% of liver transplant recipients. It typically presents after the first week but can present within the first few days after transplant or present years later. Thus, its usual description as “acute” is a misnomer. The histologic criterion for the diagnosis of ACR is a periductal lymphocytic infiltrate associated with a cellular infiltrate around the central veins.85 Nevertheless, these changes may be evident to a lesser degree even in the absence of clinical abnormalities. In a graft with stable function, rejection is typically associated with a rise in serum total bilirubin concentration associated with elevations in the circulating levels of aminotransferases and canalicular enzymes. Other clinical findings include signs of the sepsis syndrome, diarrhea, suddenly increasing ascites, eosinophilia, thrombocytopenia, and laboratory evidence of hemolysis. Chronic rejection, also a misnomer because it may occur at any point, is manifested by arteriopathy and vanishing bile ducts. Its presentation is insidious, and signs of terminal liver disease may develop slowly.

Immunosuppression

The approach to rejection is divided into two phases: prophylaxis and treatment.86 Prophylaxis is achieved by administering a combination of corticosteroids and cyclosporine (Neoral) or tacrolimus. These agents inhibit interleukin (IL)-2 expression and block T-cell recruitment. They offer a selective approach to immunosuppression in solid-organ transplantation. Prospective randomized trials comparing tacrolimus-based and cyclosporine-based regimens demonstrate that tacrolimus affords better rejection prophylaxis, is associated with less steroid-resistant rejection and need for OKT3,87,88 and is less costly when medical care in the first posttransplant year is considered.89

Azathioprine, used before the advent of newer immunosuppressive agents, is reserved for patients with recurrent rejection episodes or for those unable to tolerate the newer agents. Mycophenolate mofetil is hydrolyzed in vivo to mycophenolic acid. This compound inhibits inosine monophosphate dehydrogenase, resulting in selective inhibition of T- and B-cell proliferation.90 Mycophenolate mofetil is more expensive than azathioprine and has GI side effects (diarrhea) but less bone marrow toxicity. Data from a prospective randomized trial that enrolled liver transplant recipients indicates that combined tacrolimus, prednisone, and mycophenolate is no more toxic than tacrolimus and prednisone and that the three-drug cocktail may facilitate a reduction in tacrolimus dose.91 Newer immunosuppressive agents and techniques are under development. The current regimen at Mayo Clinic Jacksonville for prophylaxis is outlined in Table 197-4. Calcineurin inhibition with tacrolimus or cyclosporine is the cornerstone of treatment. Corticosteroids are administered intraoperatively and throughout the early postoperative period. Early introduction of mycophenolate allows a reduction in tacrolimus dose.92 Sirolimus has been associated with delayed wound healing and hepatic artery thrombosis when administered in the early postoperative period. When introduced later in the transplant course, it enables reduction or elimination of calcineurin inhibition. Thymoglobulin and IL-2 receptor (IL-2r) antagonists may be used for induction of immunosuppression, which allows for delayed introduction of calcineurin inhibitors and/or more rapid steroid taper; this is particularly useful in patients with renal impairment at the time of transplantation.

Liver biopsy may be driven by clinical changes or by protocol on day 7. The latter affords a better margin of safety/reassurance that patients with subclinical rejection will be identified and treated aggressively, enabling a less intensive immunosuppressive strategy to be successful for the remainder. Significant complications may result from liver biopsy, and this may outweigh any benefit in well-established programs with careful monitoring. Mild rejection requires no specific treatment other than up-titration of calcineurin inhibition. Moderate to severe rejection is treated initially with corticosteroids: 1000 mg of methylprednisolone is administered over a 4-day period (day 0, 500 mg; day 2, 250 mg; day 4, 250 mg). A follow-up liver biopsy is performed on the fifth day. If rejection persists, treatment with 2000 mg of methylprednisolone is given over the next 4 days (day 0, 1000 mg; day 2, 500 mg; day 4, 500 mg). Persistent rejection deemed “steroid resistant,” represents a less than 5% incidence and is treated with thymoglobulin (as OKT3 is no longer available).9397

The major side effects of cyclosporine and tacrolimus are similar: both cause significant nephrotoxicity and neurotoxicity.98 More than 90% of patients99 sustain some degree of renal injury, which is manifested clinically as azotemia. Renal dysfunction is a consequence of the hemodynamic insults of the procedure and/or side effects of calcineurin inhibitors. Ten percent of OLTX patients require some form of renal replacement therapy postoperatively, and a few require long-term hemodialysis. Neurotoxicity is more evident in the elderly and compounded by serum electrolyte disturbances, particularly hyponatremia and hypomagnesemia.100 Neurologic dysfunction ranges from a mild expressive aphasia to tremors, confusion, coma, and seizures. Other side effects of cyclosporine, such as hypertension and hirsutism, occur less commonly with tacrolimus. Because tacrolimus is a more potent agent, many patients are able to have the dose of corticosteroids tapered, if not completely discontinued.101,102

Abnormal liver function can be a complication of serious systemic illness. For example, hyperbilirubinemia can occur in patients with sepsis and is known as cholestasis lenta. However, jaundice may occur with the development of pneumonia or may herald the presence of an abscess. Other systemic processes such as disseminated fungal infections (caused by Candida spp. or Aspergillus) and viral infections such as those caused by cytomegalovirus, herpes simplex, or herpes zoster virus may result in profound derangements of liver function. Another systemic process that can affect the liver is lymphoma. Non-Hodgkin’s lymphomas can develop after solid-organ transplantation; these malignancies are called posttransplant lymphoproliferative disease. This disease is a consequence of T-cell suppression and may be mediated by Epstein-Barr virus. Polyclonal disease may respond to reduction in immunosuppression and antiviral therapy. Monoclonal disease may require chemotherapy as well for control.

image Hemodynamic Changes

The characteristic hemodynamic changes of ESLD resolve slowly after OLTX. The exact timing is unresolved, and the controversy likely reflects the preoperative state of some of the patients. Thus, problems resolve more slowly in patients with profoundly deranged liver function and MODS than in recipients who are less ill at the time of transplantation. A vasodilated hyperdynamic state is typical of liver failure103107 and rarely normalizes in the immediate postoperative period. Patients who are unable to mount a hyperdynamic response fare worse. Some recipients have preexisting cardiac dysfunction due to ischemic damage or restrictive cardiomyopathy secondary to amyloidosis or hemochromatosis; these patients are unable to increase stroke volume and cardiac output in response to vasodilation. Similarly, patients with sepsis have a higher mortality if they fail to (1) increase ventricular end-diastolic volume to preserve stroke volume as ejection fraction falls and (2) increase heart rate to increase cardiac output.108 Elevated central venous pressures (CVPs) are transmitted to the hepatic vein and through the liver. Hepatic congestion results in impaired clearance of bacteria, endotoxin, and cytokines. Elevated hepatic venous pressures are reflected in elevated portal pressures, which increase bacterial translocation and endotoxemia, further compromising graft function. Resuscitation must be guided by measurement of CVP. The etiology of hypotension should be classified as cardiac—a consequence of inadequate preload or impaired contractility—or loss of arterial tone.

Management of hypotension requires immediate restoration of adequate circulating volume, usually to a CVP of less than 12 mm Hg. Inotropic support, using dobutamine or epinephrine, should be added if cardiac output remains low despite volume loading. More typically, patients with liver failure are hyperdynamic and vasodilated. In the distributive shock of liver failure, as in septic shock, norepinephrine restores regional blood flow more effectively than dopamine. Low-dose vasopressin (0.04 unit/min) effectively restores perfusion pressure in patients with liver failure. However, vasopressin reduces portal flow and hence hepatic perfusion; these effects obviously might be undesirable in transplant recipients with compromised portal flow. Right ventricular function may be gauged using echocardiography or estimating ejection fraction using a pulmonary artery catheter equipped with a rapid-response thermistor (REF catheter [Edwards Lifesciences]). Marked arterial vasodilation, however, also should prompt an evaluation to exclude a focus of inflammation, infection, pancreatitis, or graft rejection.

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