Liver transplantation: procedure, prognosis

Liver transplantation is the second most common solid organ transplant. Indications include liver cirrhosis (70% of transplants in the United States, 60-70% of which are related to hepatitis C); fulminant liver necrosis (about 8%); hepatocellular carcinoma (about 7%); biliary atresia or metabolic disorders, mainly in children (about 3%) and other cholestatic (eg, primary sclerosing cholangitis) and noncholestatic (autoimmune hepatitis) disorders (about 8%). For patients with hepatocellular carcinoma, transplantation is indicated for one tumor less than 5 cm or up to 3 tumors less than 3 cm (Milan criterion) and for some fibrolammellar tumor types. In patients with liver metastases, transplantation is indicated only for neuroendocrine tumors in the absence of extrahepatic growth after removal of the primary tumor.

Absolute contraindications include elevated intracranial pressure (>40 mmHg) or low cerebral perfusion pressure (<60 mmHg), sepsis, advanced or metastatic hepatocellular carcinoma; all of these conditions are associated with poor outcomes during or after transplantation.

Almost all donor organs are obtained from heart-beating, ABO- and liver-size-matched cadaveric donors. About 500 transplants per year come from living donors, who may survive without a right lobe (in adult-to-adult transplants) or without a lateral segment of the left lobe (in adult-to-child transplants). The advantages of a living donor for the recipient include shorter waiting times, shorter cold ischemia periods for explanted organs, and the ability to schedule transplantation to best suit the patient's condition. Disadvantages for the donor include a mortality risk of 1:300–1:400 (compared to 1:3,300 for living kidney donations) and complications (especially bile leakage) in one-quarter of cases when lobar resection is performed rather than segmental resection. Living donors are at risk of psychological harm. A small number of organs are obtained from donors who did not die from heart disease.

Recipient risk factors associated with transplantation (from living or deceased donors) include donor age over 50 years; hepatic steatosis; elevated liver function tests, bilirubin, or both; prolonged intensive care unit stay; hypotension requiring vasopressors; and hypernatremia. Transplantation from a female donor to a male recipient also increases risk. However, because the imbalance between demand and resources in liver transplantation is large (and is increasing because of the prevalence of hepatitis-associated cirrhosis), organs from donors over 50 years of age, organs with short cold ischemia time, organs with fatty infiltration, and organs with viral hepatitis (for transplantation into recipients with viral hepatitis-induced cirrhosis) are increasingly being used. Additional technologies to increase organ resources include split liver transplantation, in which a deceased donor liver is divided into right and left lobes or a right lobe and left lateral segment (performed in or ex situ) and divided between two recipients; and domino transplantation, a rare technique in which a liver from a deceased donor is transplanted into a recipient with infiltrative disease (eg, amyloidosis) and the explanted diseased liver is transplanted into an older patient who can live with a diseased liver but is not expected to survive long enough to experience the adverse effects of graft dysfunction.

Despite these innovations, many patients die while awaiting transplants. Liver-preserving techniques (extracorporeal perfusion with cultured hepatocyte suspensions or long-term hepatoma cell lines) are used in some centers to keep patients alive until a suitable liver is found or acute dysfunction resolves. To optimize the allocation of available organs to patients on a national list, a prognostic index is calculated based on creatinine, bilirubin, and INR (for adults) and on age, serum albumin, bilirubin, INR, and growth failure (for children). For patients with hepatocellular carcinoma, this index includes tumor size and waiting time (it increases with each component). Patients with higher indices are more likely to die and have an advantage in receiving organs from weight- and ABO-matched donors.

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Liver transplant procedure

The liver of cadaveric donors is removed after laparotomy of the abdominal cavity confirming the absence of abdominal diseases that may interfere with transplantation. In living donors, lobar or segmental resection is performed. The explanted liver is perfused and stored in a cold preservative solution for no more than 24 hours before transplantation; with increasing storage time, the incidence of graft dysfunction and ischemic biliary damage increases.

Recipient hepatectomy is the most traumatic part of the procedure, as it is often performed in patients with portal hypertension and coagulation disorders. Blood loss during surgery can exceed 100 units, but the use of cell-preserving equipment and autotransfusion techniques can reduce allogeneic transfusion requirements to 10-15 units. After hepatectomy, an end-to-side anastomosis is created between the suprahepatic vena cava of the donor graft and the inferior vena cava of the recipient (piggy-back technique). An anastomosis is then created between the portal veins of the donor and recipient, the hepatic arteries, and the bile ducts. With this technology, there is no need for a heart-lung machine to direct portal venous blood into the systemic venous circulation. Heterotopic placement of the liver provides an "additional" liver and helps to avoid some technical difficulties, but the results are unsatisfactory, so this technology is at the experimental development stage.

Immunosuppressive therapy courses may vary. Typically, IL-2 receptor monoclonal antibodies with calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil, and glucocorticoids are started on the day of transplantation. Except for recipients with autoimmune hepatitis, glucocorticoids are tapered over several weeks in most patients and are often stopped within 3 to 4 months. Compared with other solid organ transplants, liver transplantation requires the lowest doses of immunosuppressants.

For unknown reasons, liver allografts are rejected less aggressively than other organ allografts; hyperacute rejection is less common than expected in patients previously sensitized to HLA and ABO antigens, and immunosuppressants can often be tapered relatively quickly and effectively stopped. Most cases of acute rejection are mild and self-limited, occur within the first 3–6 months, and do not threaten graft survival. Risk factors for rejection include young recipient age, older donor age, significant HLA differences, prolonged cold ischemia time, and autoimmune disorders; poorer nutritional status (eg, due to alcoholism) appears to be protective.

Symptoms and objective signs of rejection depend on its type. Symptoms of acute rejection are observed in almost 50% of patients; symptoms of chronic rejection - in 2%.

The differential diagnosis of acute rejection includes viral hepatitis (eg, cytomegalovirus, Epstein-Barr virus; recurrent hepatitis B, C, or both), calcineurin inhibitor intoxication, and cholestasis. If the diagnosis is difficult to establish clinically, rejection can be diagnosed by percutaneous needle biopsy. Suspected rejection is treated with intravenous glucocorticoids; antithymocyte globulin and OKTZ are the drugs of choice when glucocorticoids are ineffective (in 10-20%). Retransplantation is performed when rejection is refractory to immunosuppressants.

Immunosuppressants promote recurrence of viral hepatitis in patients with hepatitis-related cirrhosis before transplantation. Hepatitis C recurs in almost all patients; viremia and infection are usually subclinical but may cause acute hepatitis and cirrhosis. Risk factors for re-infection include certain characteristics of the recipient (older age, HLA type, hepatocellular carcinoma), donor (older age, fatty liver, prolonged ischemic time, living donor), virus (high viral load, genotype 1B, impaired interferon response), and post-procedural factors (immunosuppressant doses, treatment of acute rejection with glucocorticoids and OKTZ, cytomegalovirus infection). Standard treatment (see p. 204) is of little effect. Hepatitis B recurs in all but is successfully treated with immunoglobulin and lamivudine; co-infection with hepatitis D appears to provide protection against relapse. ' V

Early complications (within 2 months) of liver transplantation include primary dysfunction in 5-15% of cases, biliary dysfunction (eg, ischemic anastomotic strictures, bile leaks, ductal obstructions, leaks around a T-tube) in 15-20%, portal vein thrombosis in 8-10%, hepatic vein thrombosis in 3-5% (especially in patients receiving sirolimus), mycotic hepatic artery or pseudoaneurysm, and hepatic artery rupture. Typical symptoms include fever, hypotension, and elevated liver enzymes.

The most common late complications are strictures of the intrahepatic or anastomotic bile ducts, which present with symptoms of cholestasis and cholangitis. Strictures are sometimes treated endoscopically or by percutaneous transhepatic cholangiographic dilation, stenting, or both, but often these complications require retransplantation.

Liver transplant prognosis

At 1 year, survival rates for living donor livers are 85% for patients and 76% for grafts; for deceased donor livers, the rates are 86% and 80%, respectively. Overall patient and graft survival rates are 78% and 71% at 3 years and 72% and 64% at 5 years. Survival is more common in chronic liver failure than in acute liver failure. Patient death after 1 year is rare and is more likely to be due to recurrent disease (eg, cancer, hepatitis) than to posttransplant complications.

Recurrent hepatitis C leads to cirrhosis in 15-30% of patients within 5 years. Liver lesions associated with autoimmune diseases (eg, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis) recur in 20-30% of patients within 5 years.