Liver grafts are harvested from deceased or living donors. Cadaveric livers are procured after brain or cardiac death. Because of an increasing number of patients who die waiting for a transplant, efforts to expand the donor pool include donation after cardiac death (DCD), harvesting marginal organs from cadavers with extended donor criteria, and procuring partial livers from living donors. DCD is the fastest growing source of transplant organs in the United States. Upon cardiac death (defined as the irreversible cessation of circulatory and respiratory function), the liver is harvested after a mandatory waiting period of 1 to 5 minutes. Warm ischemic time begins when the waiting period starts and ends when the liver is flushed with cold preservative solution. Transplantation of a DCD-donor liver that has been exposed to a longer warm ischemic time than a graft from a brain-dead donor may be associated with perioperative complications such as vascular- and biliary-related lesions and early graft dysfunction. Ideal organs have shorter warm and cold ischemic times and are harvested from hemodynamically stable donors younger than 50 years of age who are free of hepatobiliary or renal disease, infection, and cancer.

Extending donor criteria (age older than 65 years; DCD; positive viral serology; split liver; hypernatremia; or prior carcinoma, steatosis, or high-risk behaviors) to harvest organs with initial poor function or primary nonfunction expands the donor pool.

A related or unrelated healthy individual may donate a portion of the liver for transplantation. Usually, the right hepatic lobe is removed from a healthy individual and transplanted
into an adult recipient. Transplantation of the smaller left hepatic lobe into pediatric or very small adults may decrease the incidence of complications in the donor. This chapter focuses on cadaveric liver transplantation into adult recipients.

Patients with acute liver failure (ALF), decompensated cirrhosis, or hepatocellular carcinoma are candidates for liver transplantation. In the United States, alcoholic liver disease is the most common cause of end-stage liver disease (ESLD), but cirrhosis from hepatitis C is the most common indication for orthotopic liver transplant. With the rise of the obesity epidemic, nonalcoholic steatohepatitis (NASH) is the third most common indication for liver transplantation. Specific indications for transplantation include recurrent cholangitis in patients with primary sclerosing cholangitis or intractable pruritus in patients with primary biliary cirrhosis. Uncommon indications for liver transplantation include hepatic tumors such as carcinoid tumors and hepatic adenoma, metabolic disorders such as α₁-antitrypsin deficiency, vascular disorders such as Budd-Chiari syndrome, cystic fibrosis, hemochromatosis, amyloidosis, sarcoidosis, hyperoxaluria, and adult polycystic liver disease. Biliary atresia is the most common indication for pediatric liver transplantation.

Most surgeons will not offer transplantation to patients with severe cardiopulmonary or neurologic disease, significant hemodynamic instability, sepsis, extrahepatic malignancy, active alcohol or drug use, or unfavorable psychosocial circumstances. The decision to offer transplantation considers age and infection with human immunodeficiency virus.

In the absence of transplantation, ALF leads to death. ALF is defined by the absence of chronic liver disease, acute hepatitis (elevation in transaminases with an elevation in INR), encephalopathy, and illness less than 26 weeks. The most common causes of ALF are acetaminophen toxicity (39%), indeterminate (18%), idiosyncratic (19%), and acute viral hepatitis (12%, usually hepatitis B). Other etiologies include drugs (phenytoin and halothane), autoimmune disease, Wilson disease, Budd-Chiari syndrome, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), acute fatty liver of pregnancy, toxins (i.e., trichloroethylene and tetrachloroethane in cleaning solvents and sniffed glue), and Amanita phalloides, the “deathcap” mushroom that grows wild in parts of the United States.

Grafts from deceased donors are offered to patients with the highest risk of death. Since 2002, the Model for End-stage Liver Disease (MELD), a validated and widely used prognostic tool that estimates disease severity and 3-month survival in patients with chronic liver disease, prioritizes organ allocation (Fig. 16.1). The MELD score ranges from 6 to 40 points and is calculated from the patient’s serum bilirubin, serum creatinine, and INR.

The cardiovascular system of patients with ESLD mimics the hyperdynamic circulatory changes of patients with sepsis. Tachycardia, elevated cardiac output, low arterial blood pressure, and low systemic vascular resistance are characteristic. Enhanced endogenous production or diminished hepatic clearance of vasodilating substances, such as nitric oxide, carbon monoxide, and endogenous cannabinoids, and the inflammatory response to bacterial
translocation cause splanchnic arterial vasodilation. Increased venous capacitance from formation of portosystemic shunts because of portal hypertension increases venous capacitance and contributes to a hyperdynamic circulation. During the perioperative period, the patient’s circulatory system may be challenged with shunt insertion or greater afterload from surgical stress, unmasking an underlying cirrhotic cardiomyopathy. Echocardiography shows impaired myocardial function similar to that found in septic patients. This condition is also characterized by QT prolongation and systolic and diastolic dysfunction. Reduced β-receptor function may explain these findings.

Systemic conditions such as hemochromatosis (ventricular hypertrophy with increased end-diastolic and end-systolic volumes), amyloidosis (restrictive cardiomyopathy), Wilson disease (supraventricular extrasystolic beats), and alcoholism (systolic and diastolic dysfunction) can affect liver and cardiac function. Patients with portal hypertension may develop portopulmonary hypertension and right ventricular dysfunction. A mean pulmonary artery pressure greater than 25 mm Hg at rest and a pulmonary vascular resistance greater than 240 dynes/sec/cm^-5 define portopulmonary hypertension.

Patients with AKI and cirrhosis have more complications and increased risk of mortality after liver transplantation than those without renal failure. Gastrointestinal bleeding, diarrhea from infection or lactulose administration, and diuretic medications change circulatory function via hypovolemia and can cause renal injury. As cirrhosis progresses, a reduction in systemic vascular resistance causes compensatory activation of the renin-angiotensin and sympathetic nervous systems, which leads to ascites, edema, and vasoconstriction of the intrarenal circulation and renal hypoperfusion.

Hepatorenal syndrome (HRS) is caused by functional renal vasoconstriction in response to splanchnic arterial vasodilation. Although histologic findings and diagnostic tests for HRS are lacking, diagnostic criteria are used to categorize two types of HRS. Criteria for HRS include (1) cirrhosis with ascites, (2) serum creatinine greater than 1.5 mg per dL, (3) no improvement of creatinine after 2 days of diuretic withdrawal and volume expansion with albumin, (4) absence of shock, (5) no current or recent treatment with nephrotoxic drugs, and (6) absence of parenchymal kidney disease. Type I HRS involves rapid and progressive impairment of renal function (usually the result of an acute insult such as spontaneous bacterial peritonitis or a large volume paracentesis) with a doubling of the initial serum creatinine to a level greater than 2.5 mg per dL or a 50% reduction in the 24-hour creatinine clearance to lower than 20 mL per minute in less than 2 weeks. The development of type I HRS is associated with a short-term mortality of more than 50%. Patients with type II HRS have impaired renal function and a serum creatinine greater than 1.5 mg per dL and do not meet the criteria for type I HRS. Compared with patients diagnosed with prerenal failure, patients with HRS lack a renal response to a 1.5-L volume challenge. Distinguishing between HRS and acute tubular necrosis is difficult. A fractional excretion of sodium less than 1% suggests tubular function and favors a diagnosis of HRS. The presence of renal tubular epithelial cells in urinary sediment favors a diagnosis of acute tubular necrosis.

The administration of terlipressin, a vasopressin analogue, along with intravenous albumin has been shown to have some benefit in patients with type I HRS. Medical management of HRS is marginally effective, but liver transplantation can reverse HRS. Kidneys transplanted from patients with HRS function normally in new hosts, suggesting the essential role of hepatic disease in the pathogenesis. Up to 40% of patients with HRS do not recover
kidney function after transplantation. In these cases, systemic inflammation with hyperbilirubinemia may contribute to irreversible structural damage to the kidney.

Patients with advanced cirrhosis have decreased effective blood volume and then circulatory dysfunction. They develop hypervolemic hyponatremia from increased secretion of antidiuretic hormone, which acts on the vasopressin-2 receptors of the renal tubular collecting duct to impair excretion of solute-free water. These patients have expanded extracellular volume, ascites, and edema.

Patients who develop hypovolemic hyponatremia via loss of extracellular fluid from the kidneys (overdiuresis) or gastrointestinal tract rarely have ascites or edema. These patients may have prerenal failure from low plasma volume and dehydration or hepatic encephalopathy from a rapid reduction in serum osmolality.

Hepatic encephalopathy is a neuropsychiatric complication of acute and chronic liver disease with features that range from mild confusion to cerebral edema with intracranial hypertension. Patients have disturbances in consciousness, cognitive abilities, behavior, neuromuscular function, concentration, reaction time, memory, and/or electroencephalogram readings. The pathogenesis of hepatic encephalopathy is not understood, but most theories implicate elevated levels of ammonia, a gut-derived neurotoxin, which is shunted to the systemic circulation from the portal system. Bacteria in the gut produce ammonia, which crosses the blood-brain barrier into astrocytes that detoxify it to glutamine. Astrocytes regulate neurotransmission, but their function is decreased when they swell because of increased concentrations of intracellular glutamine. High serum ammonia levels characterize patients with hepatic encephalopathy, even though the degree of elevation of ammonia does not correlate with neurologic severity. This observation suggests that other factors, such as hyponatremia, gastrointestinal bleeding, and infection contribute to the development of hepatic encephalopathy. Left untreated, cerebral edema can progress to intracranial hypertension and herniation of the brain. Multiple grading scales assess the severity of hepatic encephalopathy. The most common scales are the West Haven Criteria (Conn Score), which has grades 0 through 4 and the Glasgow Coma Scale (GCS).

Patients with ESLD have hemostatic changes that promote both bleeding and thrombosis. Inadequate synthesis of all coagulation factors (except for von Willebrand factor), thrombocytopenia, platelet function defects, dysfibrinogenemia, and elevated tissue plasminogen activator (tPA) levels cause bleeding. Elevations of von Willebrand factor and factor VIII and decreased levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), protein C, protein S, antithrombin, α2-macroglobulin, plasminogen, and heparin cofactor II favor thrombosis.

Factors VII, X, V, II (prothrombin), and I (fibrinogen) have a short half-life (hours to days) and are synthesized solely in the hepatocytes making possible a “semi-real time” evaluation of the liver’s synthetic function. Although patients with liver disease can have abnormal prothrombin times (PTs) from decreased production of procoagulant factors, the rebalanced state of pro- and anticoagulants in patients with liver disease makes the PT an unreliable tool for evaluating tendency to bleed or clot.

Levels of fibrinogen, an acute phase reactant, are normal or increased in liver disease. Patients with severe hepatic dysfunction, however, may synthesize fibrinogen poorly, which increases the risk of bleeding. Although high concentrations of fibrinogen are found in patients with chronic hepatitis, cholestatic jaundice, and hepatocellular carcinoma, clot formation is not enhanced because fibrinogen is dysfunctional. Hyperfibrinolysis (from increased levels of tPA and reduced levels of thrombin-activatable fibrinolysis inhibitor [TAFI] and plasmin inhibitor) has been observed in cirrhotic patients, but its association with bleeding is unclear. Hypofibrinolysis (from increased levels of plasminogen activator inhibitor [PAI] and reduced levels of plasminogen) may restore the balance of fibrinolysis.

Thrombocytopenia and platelet dysfunction are characteristic of ESLD. Thrombocytopenia results from several factors: hypersplenism, which sequesters platelets; consumption of platelets during systemic intravascular coagulation; and impaired hepatic synthesis of thrombopoietin, which produces platelets in the bone marrow. Defective signal transduction; uremia from AKI; and intrinsic defects of adenosine diphosphate (ADP), arachidonic acid, collagen, and thrombin prevent platelet aggregation.

There may be little evidence of deranged coagulation when normal hepatic parenchyma is preserved, such as in an isolated hepatoma.

Potential causes of preoperative hypoxemia and respiratory failure in patients with cirrhosis includes atelectasis from the compressive effects of ascites, hepatic hydrothorax, hepatopulmonary syndrome (HPS), and underlying chronic pulmonary disease. Muscle wasting and intra-abdominal hypertension from ascites increase the work of breathing.

Ascites fluid can enter the pleural space through small channels in the diaphragm to cause a hepatic hydrothorax (usually on the right side). Negative intrathoracic pressure during inspiration facilitates movement of fluid from the peritoneum to the pleural space to minimize ascites.

A diagnosis of HPS is considered in patients without cardiopulmonary disease who have a PaO₂ less than 60 mm Hg. The triad of liver disease and/or portal hypertension, widened age-corrected alveolar-arterial oxygen gradient (more than 15 to 20 mm Hg) while breathing room air, and documented intrapulmonary vascular dilation (IPVD) define HPS. Enhanced production or impaired hepatic clearance of endogenous vasodilators (i.e., nitric oxide, carbon monoxide, vasodilator prostaglandins, substance P) or inhibition of vasoconstrictive substances (i.e., tyrosine, serotonin, and endothelin) by a damaged liver may cause IPVD. IPVD causes hypoxemia via ventilation/perfusion mismatching, intrapulmonary shunt physiology, and diffusion limitation. Patients with HPS often complain of dyspnea and fatigue; they
may have clubbing and spider angiomata on physical examination. Patients may experience platypnea (dyspnea in the upright position relieved by recumbency) or have orthodeoxia (arterial oxyhemoglobin desaturation in the upright position). Preferential perfusion of IPVD (while the patient is upright) may cause these clinical manifestations. Contrast-enhanced echocardiography or perfusion lung scanning with technetium-99m-labeled macroaggregated albumin detects intrapulmonary shunting suggestive of IPVD. Medical therapy for HPS has, to date, been relative ineffective. Currently, the only known treatment option for patients with HPS is a liver transplant.