Rudolph's Pediatrics, 22nd Ed.

CHAPTER 130. Liver Transplantation

Patrick J. Healey

Liver transplantation is now the accepted standard of care for the management of irreversible end-stage liver disease in children. Since the first successful liver transplant by Starzl in 1966, continuous improvements in patient selection, surgical technique and postoperative care, as well as advances in organ preservation and immunosuppression management have resulted in improved graft and patient survival. Earlier referral for transplantation, and advances in the clinical management of rejection, infection, and biliary and vascular complications have also contributed to improved outcomes.

EPIDEMIOLOGY

Each year, approximately 600 children have received a liver transplant in the United States.¹ Of these, 15% have been living donor liver transplants. In 2007, approximately 400 children were waiting for a liver transplant on the United Network for Organ Sharing (UNOS) national waiting list. The risk of death while waiting for a transplant is related to age. Young children less than 1 year old have the highest death rate of all waiting list candidates, adult or pediatric, nearly 6 times the death rate for older children and adults.

INDICATIONS FOR LIVER TRANSPLANTATION

Indications for liver transplantation are listed in Table 130-1. Liver transplantation is indicated for life threatening failure of liver function due to either chronic liver conditions or acute hepatic necrosis. End-stage liver disease because of cholestatic liver disease represents the reason that the majority of children are referred for liver transplantation. Of these, biliary atresia is the most common single diagnosis, accounting for approximately 45% of all children undergoing liver transplant.² Other common indications include metabolic liver diseases, acute liver failure, hepatic malignancy, and chronic hepatitis.

EVALUATION FOR LIVER TRANSPLANTATION

A complete understanding of the natural history of the underlying liver disease as well, as any associated extrahepatic complications or manifestations of the primary disease, is essential for the transplant hepatologist to determine if liver transplantation is appropriate. Following a decision to proceed with liver transplantation, the child’s health status should be optimized in preparation for transplant as detailed in Chapters 424 and 425, with particular attention to appropriate nutritional management, which may require supplemental enteral or parenteral nutritional support.

Laboratory tests routinely performed as part of the evaluation that may have an impact on management include the blood type; complete blood count (CBC) with differential; reticulocyte count; coagulation studies; chemistry panel; triglycerides; serum magnesium; and serologies for cytomegalovirus (CMV), HIV, HSV1 (IgM for infants), and hepatitis A, B, and C. If the patient is sexually active, a venereal disease research laboratory (VDRL) test is conducted as well. Some centers obtain a bone density study as a baseline.

A tuberculosis skin test is usually performed. Previous rubella, measles, and mumps (MMR) immunization should be confirmed or serologies obtained. Routine immunizations should be given at the earliest recommended date. All children susceptible should be given MMR if transplant is not expected within the next 4 weeks.

Imaging studies, including Doppler ultrasound of the liver and CT scan of the abdomen, provide important anatomic information regarding patency and direction of portal venous flow, the presence of spontaneous portosystemic shunts, and any variations in hepatic arterial anatomy and thereby aid the transplant surgeon in planning the transplant operation. Determination of liver volume and the presence of liver tumor are also important clinical information provided by abdominal CT or MRI scan.

A social work and/or psychological evaluation is critical to assess patient and family support needs, as well as to screen for psychosocial problems that will require careful management in order to assure a successful transplant outcome.

TIMING OF LIVER TRANSPLANTATION AND PRIORITIZATION

Causes of pretransplant morbidity and mortality include encephalopathy, infections, hepatopulmonary syndrome, hypoglycemia, and bleeding and are managed pending transplantation as detailed in Chapters 424 and 425. Children should be referred for possible liver transplantation when it becomes evident that their liver disease is progressive enough that transplantation is likely in the future, rather than waiting until severe complications ensue.

Urgency and general position on the waiting list is determined by the severity of the patient’s current liver condition and ABO blood type. Children with acute liver failure (onset fewer than 8 weeks) who are judged to be at significant risk of death from liver disease meet criteria for the most urgent listing position, status 1A. Children with chronic liver disease or hepatic malignancy who have developed severe complications of the liver disease, such as variceal bleeding, qualify for status 1B. The remainder of children awaiting liver transplant are listed according to the Pediatric End-Stage Liver Disease (PELD) score that was established based on computer mortality models that predict likelihood of death within a 3-month period and therefore a greater urgency for transplant. The PELD score is calculated incorporating objective data including bilirubin, albumin, and INR. Young children also receive additional points for age less than one year, and for growth failure. Patients with metabolic liver disease causing imminent risk of death or permanent brain injury are listed as status 1B, regardless of the PELD score. Children over 12 years are prioritized based upon the MELD score. A convenient resource for calculating MELD and PELD scores is available at http://www.unos.org/resources/meldpeldcalculator.asp.

Table 130-1. Indications for Liver Transplantation

TECHNICAL CONSIDERATIONS

The liver transplant operation includes hepatectomy of the native liver, then recipient graft vascular anastomoses of the hepatic veins or vena cava, portal vein, and hepatic artery. Biliary drainage is accomplished using either a duct-to-duct anastomosis, or a Roux-en-Y biliary-enteric anastomosis. The specific biliary drainage chosen is based on recipient’s primary liver disease, and incorporating considerations of the recipient and donor bile ducts, and donor/recipient size mismatch. In patients with biliary atresia, the Roux limb created for the Kasai portoenterostomy is typically used for donor graft drainage.

Pretransplant factors including portal hypertension, coagulopathy, previous abdominal or liver surgery, and ascites contribute to the increased risk of bleeding both intraoperatively and during the early postoperative time period. Severity of recipient liver disease, nutritional status, and any history of intra-abdominal infections also increase the risk of posttransplant complications.

The transplant liver graft may be a whole liver or a lobar or segmental graft. A single adult-sized liver graft may be divided for transplantation of two grafts into two recipients, the split-liver graft (Fig. 130-1). Split-liver techniques represent true expansion of the donor pool. Donor/recipient matching typically includes ABO blood type matching and size matching. In higher-urgency transplants, such as for fulminant liver failure, nonidentical and ABO-incompatible liver transplants have been done with good success. Living, related donors are also considered but the significant risks to the donor must be taken into account.³ Donor/recipient size mismatch may be exacerbated by edema of the graft and the recipient’s bowel and abdominal wall, and preclude primary closure of the transplant incision. In order to avoid abdominal compartment syndrome, a temporary patch and staged abdominal closure may be necessary.

FIGURE 130-1. A single adult-sized liver graft may be divided for transplantation of two grafts into two recipients, the split-liver graft.

POSTTRANSPLANT MANAGEMENT

The management of the child immediately following liver transplant is challenging. Careful fluid and electrolyte management, hemodynamic and ventilatory support, and nutrition and pain management are necessary to assure recovery from the transplant operation. The risk of intra-abdominal bleeding is substantial because of the extensive dissection involved in the transplant, vascular anatomosis, and extreme coagulopathies. Bleeding may manifest as hypotension with a falling Hgb, or bloody drainage from drains. This may require immediate surgical intervention. Coagulopathy not associated with severe bleeding should be monitored but correction with transfusion of fresh frozen plasma (FFP) or platelets should be avoided if possible because of the risk of vascular thrombosis of the portal vein or hepatic arterial inflow that can result in acute graft failure. Preoperative issues such as hepatopulmonary syndrome, and cerebral edema may further complicate postoperative management. The preoperative conditions, specific considerations because of the transplant and posttransplant issues that need to be considered during postoperative management are listed in Table 130-2.

Recovery of liver graft function is assessed clinically by physical and neurological exam. Serial blood tests will demonstrate the resolution of the ischemia/reperfusion graft injury with normalization of transaminases and clearance of jaundice usually within the first week, and spontaneous correction of coagulopathy within the first few days. Doppler ultrasounds are obtained frequently to assess vascular flows into and away from the liver graft. Overall improvement in fluid balance, hemodynamics, pulmonary function and renal function are also good clinical indicators of a recovering liver graft.

Table 130-2. Factors Impacting upon Early Posttransplant Care

Immunosuppression is typically started intraoperatively and continued daily. The most common immunosuppression strategies employ an induction agent, and a maintenance regimen often including a calcineurin inhibitor and steroids. Monoclonal antibody (basiliximab or daclizumab) directed at the IL-2 receptor, CD25, is the most common strategy to induce a state of immunologic unresponsiveness against the donor. A polyclonal antibody induction using antithymocyte globulin may also be selected in situations of increased immunologic risk, or with the goal to decrease maintenance immunosuppression. Tacrolimus is the most common agent for maintenance immunosuppression, and is dosed based on targeted serum trough levels. Steroid dosing is typically tapered from the time of transplant down to a baseline dose over the first few months following transplant. Steroid minimization strategies, and discontinuation of steroids at some interval posttransplant are increasingly utilized in pediatric liver recipients.

COMPLICATIONS OF LIVER TRANSPLANTATION

Complications following liver transplantation are relatively common and vary in etiology and in risk to graft and patient survival. They must be expected and promptly recognized to assure appropriate intervention. Pretrans-plantation morbidities alter the likely complications, as do factors including the age of the patient, type of graft, infection and immuno-suppression toxicity.

PRIMARY GRAFT NONFUNCTION

Primary graft nonfunction is an uncommon (<5%), but life-threatening complication, thought to be related to ischemia/reperfusion injury, and occurs more frequently in children than in adults.^4,5 Risk factors include graft steatosis, and prolonged ischemia time, and extremes of donor age. Clinically, in the immediate post-transplant period, the liver has poor bile flow, significant elevation of transaminases, and persistent lactic acidosis and coaagulopathy. Retransplantation is the only known effective treatment at this time.

HEPATIC ARTERY THROMBOSIS

Hepatic artery thrombosis (HAT) is the most common vascular complication, and occurs in up to 10% of pediatric liver recipients.⁴ HAT may result in biliary necrosis, presenting early as bile leak or later as biliary stricture, and most commonly occurs within the first 2 weeks after transplant. The incidence of HAT is highest in small children less than age 1, and may lead to retransplantation in up to 15% of cases. Risk factors for HAT include technical factors, poor arterial inflow, graft edema, and hypercoaguable conditions. Liver graft function may be normal, or may be significantly impaired. Absent or markedly diminished arterial signal on Doppler ultrasound is the initial diagnostic finding. Re-exploration with arterial thrombectomy or thrombolysis and revision is the primary management technique. Systemic anticoagulation is maintained after reconstruction but hepatic necrosis or biliary stricture may still result.

PORTAL VEIN THROMBOSIS

Biliary complications occur in up to 15% of pediatric liver transplant recipients, with an increased incidence reported in recipients of reduced-liver, split-liver, and live-donor liver transplants.⁶ Bile leak and stricture most commonly develop following an ischemic injury, either related to graft recovery or preservation or because of hepatic artery thrombosis. Signs of peritonitis and intra-abdominal infection may suggest bile leak, whereas biliary obstruction often presents with jaundice, elevated liver function tests, and fever. Percutaneous biliary catheter placement in interventional radiology for management of strictures, drainage of abscesses and bile collections is the preferred initial management, though surgical exploration, drainage, and reconstruction may be required.

BILIARY COMPLICATIONS

Biliary leaks and strictures occur in up to 15% of children following liver transplantation, and are even more frequent in those following an episode of hepatic artery thrombosis if the graft survive.⁷Hepatobiliary scintigraphy may be useful to identify leaks or strictures.⁸

Percutaneous transhepatic cholangiography, dilation, and stent placement are useful for diagnosis and therapy.

REJECTION

Acute cellular rejection is the most common complication following liver transplantation and may occur in up to 60% of children within the first 3 years. More than 70% of these events occur in the first 6 months posttrans-plant.⁹Children presenting with acute rejection are often asymptomatic, or may have generalized complaints such as fever or abdominal pain. Liver function tests are typically elevated, although they may be normal; jaundice is common. Diagnosis of rejection is made on liver biopsy. Histopathology reveals a lymphocytic infiltrate into the portal triads, with lymphocytic cholangitis, and endothelialitis. Central veins may also be involved. A histo-logic grading system indicating severity of rejection is used and antirejection treatment is based on the severity (see http://tpis.upmc.com/TPIShome/ for detailed description of classification system). Antirejection treatment includes methylprednisolone bolus therapy, typically tapering over 5 to 7 days. Maintenance immunosuppression is increased to higher goal levels of tacrolimus, and increased daily steroid dose, for 1 to 2 months, then tapered back to prerejection levels. Steroid-resistant episodes of rejection, or severe vascular rejection episodes, are treated with cytolytic antibody therapy using antithymocyte globulin. Additional agents such as mycophenolate mofetil may be added to maintenance immunosuppression. Acute cellular rejection is often associated with subtherapeutic immunosuppression, but typically responds completely to treatment, and rarely leads to graft loss.

A leading cause of late graft loss, however, is chronic rejection, which may result from long-standing cellular and antibody-mediated humoral antigraft response. Chronic rejection may occur in up to 30% of recipients, with the majority developing fibrosis and graft dysfunction. The hallmark of chronic rejection is bile duct loss, ductopenia, and fibrosis, seen on the liver biopsy. Patients often present with inadequate immunosuppression levels, because of nonadherence or irregular dosing, and have signs of chronic liver dysfunction including elevated liver function tests, hepatomegaly, jaundice, and portal hypertension. There is no specific therapy for chronic rejection. A steroid bolus is often given to treat any acute component of the rejection, and maintenance immunosuppression may be augmented with the addition of MMF or sirolimus. Retransplantation is necessary if the rejection is not responsive to increased immunosuppression.

INFECTION

Infection is a frequent problem after liver transplantation and is a significant cause of morbidity and mortality.¹⁰ Bacterial and fungal infections often occur early after transplant and may be related to the primary liver disease or pretransplant condition of the patient, or to intraoperative factors or events. Cholangitis may develop prior to transplant in patients with biliary cirrhosis, or biliary atresia. Complications of end-stage liver disease including malnutrition, portal hypertension, and ascites may predispose to the development of intra-abdominal infection, often from enteric gram-negative organisms. Indwelling central venous catheters also are associated with an increased risk for bacteremia. Transection of the bile duct and creation of a Roux-en-Y for biliary drainage contribute to an increased risk of postoperative bacterial and fungal infections. Intra-abdominal collections and wound infections are not uncommon in these patients.¹¹ The postoperative complications of hepatic artery thrombosis and biliary stricture also lead to an increased incidence of hepatic infarct and cholangitis, typically infected with gram-negative enteric organisms or Enterococcus.

Cytomegalovirus (CMV) is an important cause of viral infection following liver transplant, and may be symptomatic or asymptomatic. CMV infection may be a primary infection acquired from the donor liver graft in a CMV-naïve child, or a reactivation of latent infection whose development is related to immunosuppression. The routine use of prophylaxis with ganciclovir has significantly reduced the rate and severity of CMV from a historic incidence of 40% in pediatric liver recipients.¹² Onset of CMV has also been observed to occur later after transplant, as a 3-month course of prophylaxis is typically utilized. Diagnosis of CMV is made using a pp65 antigenemia assay, or a positive CMV viral culture, or by polymerase chain reaction (PCR) detection of CMV DNA. Advances in PCR techniques have led to the increased use of viral surveillance and detection of subclinical viremia, allowing earlier treatment.

Epstein-Barr virus (EBV) infection is relatively common following liver transplant and its severity and extent of disease are related to recipient immune response and to the level of immunosuppression. EBV infection may be a primary, donor-acquired, or community-acquired disease that may present like mononucloeosis or as posttransplant lymphoproliferative disorder.¹³ EBV may present clinically as a constitutional illness with fever, tonsillitis, or lymphadenopathy; leucopenia; splenomegaly; or organomegaly. The diagnosis is made by clinical exam and detection of increased EBV viral load using PCR. The availability of PCR has also contributed to the development of routine screening for asymptomatic viremia.

Alhough there is some variation across different transplant centers, nearly all centers employ a prophylaxis strategy to prevent viral and opportunistic infections following liver transplant. Perioperative antibiotics are typically used for 48 to 72 hours. Intravenous ganciclovir and oral valganciclovir are typically used for 3-month period early after transplant, during the time when the immunosuppression dosing is highest. Nystatin or another nonabsorbed antifungal agent is used to prevent oral candidiasis. Bactrim is typically used for 6 months to 1 year to prevent pneumocystis pneumonia. For further discussion of post-transplant CMV, EBV and other infections see Chapter 128.

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

Posttransplant lymphoproliferative disease (PTLD) is discussed in Chapter 128. The reported incidence in pediatric liver recipients is 5% to 14%.¹⁴ Presenting symptoms include malaise, lethargy, sore throat, weight loss, lymphadenopathy, abdominal pain, diarrhea, or graft dysfunction. On exam, lymphadenopathy, tonsillar enlargement, graft enlargement, or tenderness may be found. Tissue biopsy is necessary for diagnosis.

The mainstay of treatment of PTLD is reduced immunosuppression. Antiviral therapy with ganciclovir has been widely used but remains of unproven benefit. Chemotherapy, typically with cytoxan and steroids, is recommended for overt malignancy. Serial measurements of serum PCR for EBV and clinical assessment for the resolution of palpable disease indicate resolution of PTLD.

OUTCOMES

The most recent report of national liver transplant outcomes demonstrate 1-year, 2-year, and 3-year patient survival rates of 86.3%, 84.3%, and 83.8%, respectively. Graft survival rates were 80.2%, 76%, 75.3%, respectively. According to the Studies of Pediatric Liver Transplantation (SPLIT),¹⁵ graft loss occurring after 1 year was the result of rejection in 49% of children. Patient death after 1 year was the result of malignancy, infection, multisystem organ failure, or posttransplant lymphoproliferative disease in 61% of cases. Outcomes following liver retransplantation are inferior to those after primary liver transplant, with 1-year and 2-year patient survival rates of 67% and 65% versus 88% and 85%, respectively.¹⁶ Graft survival was also poorer. Late graft failure is relatively uncommon in children because they usually undergo transplants for disorders that did not recur in the transplanted liver. Nonadherence is a problem in long-term liver-transplant survivors, similar to other chronic disorders.