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Liver Transplantation

by Martin Hertl, MD, PhD, Paul S. Russell, MD

Liver transplantation is the 2nd most common type of solid organ transplantation. Indications include cirrhosis (70% of transplantations in the US; 60 to 70% of these cases are attributed to hepatitis C); fulminant hepatic necrosis (about 8%); hepatocellular carcinoma (about 7%); biliary atresia and metabolic disorders, primarily in children (about 3% each); and other cholestatic (eg, primary sclerosing cholangitis) and noncholestatic (eg, autoimmune hepatitis) disorders (about 8%). For patients with hepatocellular carcinoma, transplantation is indicated for 1 tumor < 5 cm or up to 3 tumors < 3 cm (Milan criteria) and for some fibrolamellar types. For patients with liver metastases, transplantation is indicated only for neuroendocrine tumors without extrahepatic growth after removal of the primary tumor.

Absolute contraindications are elevated intracranial pressure (> 40 mm Hg) or low cerebral perfusion pressure (< 60 mm Hg) in patients with fulminant hepatic necrosis, severe pulmonary hypertension (mean pulmonary arterial pressure > 50 mm Hg), sepsis, and advanced or metastatic hepatocellular carcinoma; all of these conditions lead to poor outcomes during or after transplantation.

Nearly all donated livers come from size- and ABO-matched brain-dead (deceased), heart-beating donors. Prospective tissue typing and HLA matching are not always required. ABO-incompatible liver transplants have been transplanted successfully in children < 2 yr; in older children and adults, these transplants are not used because there is a high risk of rejection and bile duct damage (ductopenia) with cholestasis, which requires retransplantation. Annually, about 250 transplants come from living donors, who can live without their right lobe (in adult-to-adult transplantation) or the lateral segment of their left lobe (in adult-to-child transplantation). Advantages of living donation for the recipient include shorter waiting times and shorter cold ischemic times for explanted organs, largely because transplantation can be scheduled to optimize the patient’s condition. Disadvantages to the donor include mortality risk of 1/600 to 700 (compared with 1/3300 in living-donor kidney transplantation) and complications (especially bile leakage) in up to one fourth. Clinicians must make every effort to prevent psychologic coercion of donors. A few livers come from deceased, non–heart-beating donors (called donation-after-cardiac-death [DCD] donors), but in such cases, bile duct complications develop in up to one third of recipients because the liver had been damaged by ischemia before donation.

Donor (deceased or living) risk factors for graft failure in the recipient include age > 50; hepatic steatosis; elevated liver enzymes, bilirubin, or both; prolonged stay in ICU; hypotension requiring vasopressors; and hypernatremia. Transplants from female donors to male recipients may also increase risk. But because imbalance between supply and demand is greatest for liver transplants (and is growing because prevalence of hepatitis-induced cirrhosis is increasing), livers from donors > 50, livers with longer cold ischemia times, those with fatty infiltration, and those with viral hepatitis (for transplantation into recipients with viral hepatitis-induced cirrhosis) are increasingly being used.

Additional techniques to increase supply include

  • Split liver transplantation: Deceased-donor livers are divided into right and left lobes or right lobe and left lateral segment (done in or ex situ) and given to 2 recipients

  • Domino transplantation: Occasionally, a deceased-donor liver is given to a recipient with an infiltrative disease (eg, amyloidosis), and the explanted diseased liver is given to an elderly recipient who can benefit from the diseased liver but is not expected to live long enough to experience adverse effects of transplant dysfunction.

Despite these innovations, many patients die waiting for transplants. Liver-assist devices (extracorporeal perfusion of cultured hepatocyte suspensions or immortalized hepatoma cell lines) are used in some centers to keep patients alive until a liver is available or acute dysfunction resolves. For distribution of available organs, patients on the national waitlist are given a prognostic score derived from creatinine, bilirubin, and INR measurements (using the Model for End-Stage Liver Disease [MELD] for adults) or from age and serum albumin, bilirubin, INR, and growth failure measurements (using the model for Pediatric End-Stage Liver Disease [PELD] for children). MELD and PELD are formulas that are used to calculate the probability of a patient dying of liver disease while waiting for a liver transplantation. Patients more likely to die are given higher priority for organs from matched donors. For patients with hepatocellular carcinoma, a score is assigned to reflect mortality risk based on tumor size and wait time.

Procedure

Deceased-donor livers are removed after exploratory laparotomy confirms absence of intra-abdominal disease that would preclude transplantation. Living donors undergo lobar or segmental resection. Explanted livers are perfused and stored in a cold preservation solution for up to 18 h before transplantation; incidence of graft nonfunction and ischemic-type biliary injury increases with prolonged storage.

Recipient hepatectomy is the most demanding part of the procedure because it is often done in patients with portal hypertension and coagulation defects. Intraoperative blood loss can total > 100 units in rare cases, but use of a cell saver machine and autotransfusion devices reduces allogeneic transfusion requirements to an average of 5 to 10 units. After hepatectomy, the suprahepatic vena cava of the donor graft is anastomosed to the recipient’s vena cava in an end-to-side fashion (piggy-back technique). Donor and recipient portal veins, hepatic arteries, and bile ducts are then anastomosed. With this technique, a bypass pump is not needed to carry portal venous blood to the systemic venous circuit. Heterotopic placement of the liver (not in its normal location) provides an auxiliary liver and obviates several technical difficulties, but outcomes have been discouraging, and this technique is still experimental.

Immunosuppressive regimens vary. Commonly, anti-IL-2 receptor monoclonal antibodies are given on the day of transplantation, with a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate mofetil, and corticosteroids. Except in patients with autoimmune hepatitis, corticosteroids can be tapered within weeks and often stopped after 3 to 4 mo. Compared with other solid organ transplantation, liver transplantation requires the lowest doses of immunosuppressants.

Complications

Liver allografts are less aggressively rejected than other organ allografts for unknown reasons; hyperacute rejection occurs less frequently than expected in patients presensitized to HLA or ABO antigens, and immunosuppressants can often be tapered relatively quickly and eventually stopped. Most episodes of acute rejection are mild and self-limited, occur in the first 3 to 6 mo, and do not affect graft survival. Risk factors include younger recipient age, older donor age, greater HLA mismatching, longer cold ischemia times, and autoimmune disorders; worse nutritional status (eg, in alcoholism) appears protective.

Symptoms and signs of rejection depend on the type of rejection (see Manifestations of Transplant Rejection by Category). Symptoms of acute rejection occur in about 50% of patients; symptoms of chronic rejection occur in < 2%.

Differential diagnosis of acute rejection includes viral hepatitis (eg, cytomegalovirus or Epstein-Barr virus infection; recurrent hepatitis B, C, or both), calcineurin inhibitor toxicity, and cholestasis. Rejection can be diagnosed by percutaneous needle biopsy if the diagnosis is unclear clinically. Suspected rejection is treated with IV corticosteroids; antithymocyte globulin and OKT3 are options when corticosteroids are ineffective (in 10 to 20%). Retransplantation is tried when rejection is refractory to immunosuppressants.

Immunosuppression contributes to recurrence of viral hepatitis in patients who had viral hepatitis-induced cirrhosis before transplantation. Hepatitis C recurs in nearly all patients; usually, viremia and infection are clinically silent but may cause active hepatitis and cirrhosis. Risk factors for clinically significant reinfection may be related to the recipient (eg, older age, HLA type, hepatocellular carcinoma), donor (eg, older age, fatty infiltration, prolonged ischemic time, living donor), virus (high viral load, genotype 1B, failure to respond to interferon), or postprocedural events (immunosuppressant doses, acute rejection treated with corticosteroids or OKT3, cytomegalovirus infection). Standard treatment (see HCV) is only marginally effective, although there is hope that newer antiviral drugs (eg, telaprevir) will improve outcomes of patients with recurrent hepatitis C. Hepatitis B recurs in all but has been successfully managed with antiviral drugs; coinfection with hepatitis D appears protective against recurrence.

Early (within 2 mo) complications of liver transplantation include

  • Primary nonfunction in 1 to 5%

  • Biliary dysfunction (eg, ischemic anastomotic strictures, bile leakage, ductal obstructions, leakage around T-tube site) in 15 to 20%

  • Portal vein thrombosis in < 5%

  • Hepatic artery thrombosis in 3 to 5% (especially in small children or recipients of split grafts)

  • Hepatic artery mycotic or pseudoaneurysm, and hepatic artery rupture

Typically, symptoms and signs of early complications include fever, hypotension, and abnormal liver function test results.

The most common late complications are

  • Intrahepatic or anastomotic bile duct strictures, which cause symptoms of cholestasis and cholangitis

After liver transplantation with DCD grafts, strictures are particularly common, occurring in about one fourth to one third of recipients. Strictures can sometimes be treated endoscopically or using percutaneous transhepatic cholangiographic dilation, stenting, or both, but they often ultimately require retransplantation.

Prognosis

At 1 yr, survival rates are

  • Living-donor grafts: 90% (patients) and 82% (grafts)

  • Deceased-donor grafts: 86% (patients) and 82% (grafts)

Overall survival rates are

  • At 3 yr: 79% (patients) and 72% (grafts)

  • At 5 yr: 73% (patients) and 65% (grafts)

Survival is better for chronic than for acute liver failure. Death after 1 yr is usually attributable to a recurrent disorder (eg, cancer, hepatitis) rather than to posttransplantation complications.

Recurrent hepatitis C leads to cirrhosis in 15 to 30% of patients by 5 yr. Hepatic disorders with an autoimmune component (eg, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis) recur in 20 to 30% by 5 yr.

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