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Pathophysiology of End-Stage Liver Disease

Although the reasons for end-stage liver disease may vary significantly, similar organ pathophysiology tends to develop in patients with advanced liver disease. Virtually all organ systems can be affected by end-stage liver disease. Consequently, a global assessment that includes consideration of all organ systems is of great importance. A significant number of the complications in patients with end-stage liver disease are the result of portal hypertension, which can be defined as portal venous pressure greater than 10 to 12 mm Hg.^[171] The pathogenesis of portal hypertension is increased hepatic resistance to flow as a result of cirrhotic changes in the liver and a hyperdynamic circulatory state secondary to systemic vasodilation and presumably volume expansion.^[172] There is some controversy whether patients with end-stage liver disease have an excessively large or depleted intravascular volume. In advanced disease, abnormalities in fluid such as altered extracellular fluid regulation and electrolyte balance are frequently manifested as ascites, pleural effusion, and edema.^[173] Subsequent changes in the splanchnic and renal circulation may lead to sodium and water retention. Abnormalities in sodium electrolyte levels are frequently observed and are often related to volume status and sodium retention; these abnormalities can result in either hyponatremia or hypernatremia.^[174] Similarly, renal dysfunction and diuretic use can cause either hyperkalemia or hypokalemia along with hypomagnesemia. Central nervous system changes in chronic liver disease are often manifested as hepatic encephalopathy, but the degree of encephalopathy may vary significantly between patients.^{[175] [176]} Ammonia levels are frequently monitored but do not seem to correlate well with the degree of hepatic encephalopathy. Increased intracranial pressure (ICP) may develop in patients with acute hepatic failure, primarily because of cerebral edema. Accurate assessment of the severity of ICP and remaining neurologic function is of paramount importance because intractable elevated ICP is a significant reason to exclude a patient from transplantation. However, there is considerable controversy whether the potential benefits of invasive monitoring for elevated ICP (e.g., bolt placements) outweigh the potential risk of devastating bleeding during placement.^[177]

In addition to the standard treatment of elevated ICP, early studies have demonstrated that the molecular adsorbents recirculating system (MARS) may be able to decrease ICP and improve cerebral perfusion pressure.^[178] Designed as a liver support device for patients in fulminant hepatic failure or the acute decompensation of chronic failure,^[179] MARS has been able to improve systemic vascular resistance and mean arterial blood pressure.^[180] Presumably, these improvements in organ function may account for the observed reduction in mortality.^{[181] [182]} Large randomized multicenter studies are currently being conducted to confirm the preliminary results of these pilot studies. MARS is based on dialysis across an albumin-impregnated membrane that removes plasma albumin-bound toxins. The dialysate is subsequently cleaned by activated charcoal and anion exchange resin.^[183]

The cardiovascular system undergoes profound changes in patients with advanced liver disease that result in a hyperdynamic state. In general, systemic vascular resistance is low, the heart rate is elevated, and arterial blood pressure is normal or slightly decreased.^[184] These hemodynamic changes result in supranormal cardiac output in patients with end-stage liver disease unless the patient is taking a β-blocker for the prevention of upper gastrointestinal bleeding. Occasionally, relatively depressed cardiac function can be associated with cirrhotic cardiomyopathy, alcoholic cardiomyopathy, or infiltrative cardiac involvement in unrecognized hemochromatosis, and these conditions should be kept in mind.^{[185] [186]}

The pulmonary system in patients with end-stage liver disease can undergo changes, and two distinct pathophysiologic syndromes that can be recognized are hepatopulmonary syndrome and portopulmonary syndrome. The principal finding in hepatopulmonary syndrome is decreased oxygenation (PaO₂ <70 mm Hg or a PAO₂ - PaO₂ gradient >20 mm Hg on room air) associated with intrapulmonary vascular dilatation. Indeed, one of the hallmarks of this syndrome is intrapulmonary shunting.^{[187] [188]} Patients with hepatopulmonary syndrome may demonstrate changes in oxygen saturation when changing from the supine and erect positions. Orthodeoxia is manifested as a decrease in oxygen saturation with a change in position from supine to standing. The presence of orthodeoxia is a significant clue for the examining physician that the patient is suffering from hepatopulmonary syndrome. Frequently but not always, hepatopulmonary syndrome resolves spontaneously over the course of months after liver transplantation.^[189]

Unfortunately, such resolution is not necessarily the case with portopulmonary hypertension, a relatively uncommon complication of portal hypertension, ^[190] and it may actually worsen after liver transplantation. Patients with liver disease experience an increased prevalence of pulmonary vascular diseases when compared with the normal population.^[191] Although cirrhosis was thought to be etiologic, portal hypertension appears to be the only consistent factor predisposing patients to the development of pulmonary hypertension.^[192] Patients are considered to have portopulmonary hypertension if they meet the following three criteria: (1) mean PAP higher than 25 mm Hg, (2) pulmonary vascular resistance (PVR) greater than 120 dyn · sec · cm^-5 , and (3) pulmonary capillary wedge pressure (PCWP) higher than 15 mm Hg in the setting of portal hypertension.^[193] Although these criteria are reasonable, diagnostic caution should be exercised because interpretation of measured hemodynamic values is limited by the hyperdynamic circulation that occurs in patients with liver disease.^[187] Portopulmonary hypertension may progress rapidly and carries high perioperative morbidity and mortality when significant. Therapeutic agents used to treat primary pulmonary hypertension not associated with liver disease have also been administered to patients with this condition, with mixed results.^{[194] [195] [196] [197] [198]}

Renal dysfunction also develops in a significant number of patients with end-stage liver disease. It is usually the result of primary renal disease, acute tubular necrosis, or hepatorenal syndrome. Hepatorenal syndrome develops

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Various hemostatic abnormalities are found in patients with end-stage liver disease who present for liver transplantation. These changes can be caused by preoperative coagulation disorders or may be related to the procedure itself. Levels of procoagulant factors (II, V, VII, IX, X) and anticoagulant factors (protein C and S, antithrombin III) are frequently decreased in patients with end-stage liver disease.^{[204] [205] [206]} Thrombocytopenia as a result of hypersplenism, qualitative platelet dysfunction, and disorders of the fibrinolytic system (reduced levels of plasminogen, α₂ -antiplasmin, and factor XIII and increased plasma tissue-type plasminogen activator levels) is often encountered during the perioperative period.^[207] Although end-stage liver disease frequently increases the risk of bleeding, thrombotic complications such as portal vein thrombosis are also seen in this patient population. Indeed, several case reports and case series have demonstrated intraoperative thrombus formation in the cardiopulmonary system.^{[208] [209] [210] [211] [212]} Frequently, thrombus formation was associated with the coadministration of antifibrinolytics such as aprotinin or aminocaproic acid. It is important to recognize that a conclusive statement with regard to antifibrinolytics and thrombus formation cannot be made because of the lack of sufficient data and the absence of controlled studies.