Postoperative Hepatic Dysfunction

Definition

Clinically significant acute liver dysfunction is common after anesthesia and surgery. Major risk factors include the presence of preexisting liver disease (cirrhosis, fibrosis, or steatohepatitis), massive blood transfusion, a small remnant liver volume from massive liver resection, and perioperative liver insult (hypoxia, sepsis, drug toxicity, poor nutrition). Technical difficulties with biliary drainage or bile leak may also be contributory. Most postoperative jaundice is multifactorial in origin, is difficult to diagnose, and often requires supportive care. After elective abdominal surgery the incidence of abnormal liver function tests is 25% to 75%; however, the incidence of postoperative hepatic dysfunction is less than 1%.

Postoperative jaundice is usually evident within the first week after surgery and is not associated with acute liver failure. The normal serum bilirubin level is 0.3 to 1.1 mg/dL. Jaundice is clinically detectable when the serum bilirubin exceeds 3 to 5 mg/dL and the patient develops yellow discoloration of the sclera and skin. Increased conjugated bilirubin reflects a problem with bilirubin secretion due to hepatocellular dysfunction, intrahepatic cholestasis, or biliary tract obstruction. If the increase in total bilirubin is primarily unconjugated, the most likely cause is either hemolysis of erythrocytes producing a large bilirubin load or defects in liver uptake, transport, or conjugation of bilirubin.

Studies have shown a clear relationship between postoperative functional liver volume and the likelihood of developing clinically evident liver failure. In a patient with a healthy liver, up to 75% of the liver volume can be resected with little disturbance of liver function. The reported incidence of postresectional liver failure (PLF) varies between 0.7% and 9.1%. In the past decade the mortality rate after partial liver resection has ranged from 0% to 5%, with PLF being the main cause of death. Unfortunately, there is no consensus of a definition for PLF. In general, PLF is characterized as failure of one or more of the hepatic synthetic and excretory functions that results in hyperbilirubinemia, hypoalbuminemia, prolonged PT and serum lactate, and/or different grades of hepatic encephalopathy. On postoperative day 5, a prothrombin index less than 50% (international normalized ratio [INR] >1.7) and serum bilirubin greater than 2.9 mg/dL have been shown to be predictive of a 59% risk of mortality (sensitivity 69.6% and specificity 98.5%) in patients without underlying liver disease who have undergone major hepatic resection. In addition, a peak bilirubin of 7.0 mg/dL has been suggested as a predictor of PLF-related death.

Recognition

Owing to the large functional reserve of the liver, routine laboratory values may be normal despite significant underlying disease. Abnormal results of several common laboratory tests may loosely reflect hepatic dysfunction ( Box 168.1 ). In acute hepatic injury, PT and, to a lesser extent, total bilirubin are the best indicators of severity of disease.

PT has been used traditionally in assessment of severity of liver disease in the Child Pugh score or as INR in the MELD score (discussed later in this chapter). PT measures activity of the extrinsic coagulation pathway and requires fibrinogen, prothrombin, and factors V, VII, and X, which are synthesized in the liver. If PT is prolonged more than 3 seconds over control, this may reflect severe hepatic dysfunction, because only 20% to 30% of normal factor activity is required for coagulation. In reality, coagulation is a complex process involving the interaction of procoagulation and anticoagulation factors and the fibrinolytic system. As there is a reduction in both anticoagulant and procoagulant factors, global tests of coagulation may be normal in patients with acute and chronic liver disease. With obstructive biliary disease, the failure of bile salt secretion may result in poor absorption of vitamin K, which is a cofactor necessary for the posttranscriptional gamma-carboxylation and activation of factors II, VII, IX, and X. An INR greater than 1.5 not corrected by vitamin K within 24 hours suggests severe liver disease. A variety of more specific coagulation tests may be useful in detecting liver dysfunction (activated partial thromboplastin time, clotting time, bleeding time, thrombin time, whole blood clot lysis, plasma fibrinogen, serum fibrinogen degradation product, plasma D-dimer, euglobulin lysis time, factor assays for F XIII, protein C, protein S, and antithrombin III), as well as global hemostasis (thromboelastography, Rotem, INR liver).

Derangements in conventional markers of coagulation such as PT/INR, partial thromboplastin time, and platelet count are common and correlate with the extent of liver resection. An increase in PT/INR becomes evident within 12 hours of surgery. A corresponding decrease in platelet count and fibrinogen also occurs. Decreased synthetic function of the remnant liver and hemodilution and consumption of clotting factors are most likely responsible for this postoperative coagulopathy, which peaks 2 to 5 days after surgery.

Although tests that measure the level of serum liver enzymes are commonly referred to as liver function tests, they usually reflect hepatocyte integrity or cholestasis rather than liver function. After major liver resection, the pattern of liver function test abnormalities in the majority of patients is very predictable ( Fig. 168.1 ). The liver transaminase enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are immediately elevated due to ischemic liver injury and fall progressively, as bilirubin increases often peaking around day 4 to 6. Of the liver transaminase enzymes, ALT is the gold standard biomarker for hepatocellular injury, as it is localized solely in the cellular cytoplasm. Full assessment of enzyme abnormalities involves careful evaluation of (1) the predominant pattern of enzyme alteration (hepatocellular vs. cholestatic); (2) the magnitude of change in serum concentration (mild, <5 times the upper limit; moderate, 5 to 10 times the upper limit; severe, >10 times the upper limit); (3) the rate of change (increase or decrease over time); and (4) the nature of the course of alteration (mild fluctuation or progressive increase).

The serum ammonia concentration represents the balance between ammoniagenesis (primarily in the gut and kidney) and hepatic urea synthesis. Because the normal liver’s reserve capacity for urea synthesis is great, elevated serum ammonia concentrations usually indicate significant loss of hepatic function. Hyperlactemia and hypophosphatemia are common derangements in patients undergoing liver resection. Gluconeogenesis in the liver normally consumes 40% to 60% of lactate. During resection or stress, it produces rather than metabolizes it. As such, the arterial plasma lactate concentration is an independent predictor of morbidity and mortality, being higher in nonsurvivors. Hypophosphatemia is encountered in nearly all patients after major liver resection. The pathogenesis is poorly understood and is generally believed to be due to increased phosphate by regenerating hepatocytes or excessive urinary losses.

Jaundice is the most common and easily recognized sign suggesting hepatic dysfunction. Bilirubin is the primary end product of hemoglobin metabolism. The uptake and transport of unconjugated bilirubin into hepatocytes is followed by hepatic conjugation with glucuronide and subsequent excretion into bile canaliculi. A total bilirubin concentration greater than 1.5 mg/dL is considered abnormal. Diagnosing hyperbilirubinemia includes clinical history, physical examination, biochemical testing, and hepatobiliary imaging. Alkaline phosphatase (ALP) and bilirubin levels are routinely assessed, and the level of gamma-glutamyl transferase is often measured as an additional aid toward diagnosis in certain situations because of its high sensitivity but low specificity.

Postoperative jaundice can be categorized into three groups: (1) prehepatic (bilirubin production exceeds excretion); (2) intrahepatic (acute or subacute hepatocellular injury with or without preexisting liver disease); (3) posthepatic (cholestasis from obstruction of bile flow).