Hepatic physiology and preoperative evaluation

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Hepatic physiology and preoperative evaluation

Frank D. Crowl, MD

Patients with preexisting severe hepatic dysfunction are known to be at significant risk for experiencing perioperative death. Patients with mild to moderate hepatic dysfunction are at increased risk for death.

Some patients develop unexpected hepatic dysfunction (jaundice) in the postoperative period. The reported incidence of postoperative hepatic dysfunction, as demonstrated by abnormalities in liver function tests, is between 1 in 239 and 1 in 1091 anesthetics delivered. Interestingly, some of these patients had preexisting hepatic dysfunction that was not clinically apparent. One study found that 1 in 700 healthy asymptomatic ASA class I and II patients admitted for elective operations had unexplained abnormalities on preoperative liver function tests. After cancellation of their operations, one third of these patients developed clinical jaundice.

Metabolic function

Glucose homeostasis

The liver maintains glucose homeostasis through a combination of mechanisms: the conversion of fats and proteins to glucose by gluconeogenesis, glycogenesis (glucose → glycogen, 75 g stored in liver ∼ 24-h supply), and the release of glucose from glycogen by glycogenolysis. Insulin stimulates glycogenesis and inhibits gluconeogenesis and the oxidation of fatty acids. Glucagon and epinephrine have the opposite effect by inhibiting glycogenesis and stimulating gluconeogenesis.

Fat metabolism

Beta oxidation of fatty acids between meals provides a large proportion of body energy requirements and reduces the need for gluconeogenesis.

Protein synthesis

All plasma proteins are produced in the liver, except gamma globulins, which are synthesized in the reticuloendothelial system, and antihemophiliac factor VIII, which is produced by vascular and glomerular endothelium and sinusoidal cells of the liver. Most drugs administered by anesthesia providers are metabolized by the liver, and many of the metabolites are excreted through the biliary system.

Hepatic blood flow

Total hepatic blood flow (HBF) is approximately 100 mL·100 g⁻¹·min⁻¹, 75% of which flows through the portal vein, which is rich in nutrients from the gut but is partially deoxygenated, and can therefore supply 50% to 55% of hepatic O₂ requirements. The hepatic artery supplies 25% of HBF and 45% to 50% of hepatic O₂ requirements.

Splanchnic vessels supplying the portal vein receive sympathetic innervation from T3 through T11. Hypoxemia, hypercarbia, and catecholamines produce hepatic artery and portal vein vasoconstriction and decrease HBF. β-Adrenergic blockade, positive end-expiratory pressure, positive-pressure ventilation (increased intrathoracic pressure increases hepatic vein pressure, which in turn decreases HBF), inhalation anesthetic agents, regional anesthesia with a sensory level above T5, and surgical stimulation (proximity of surgery to the liver determines the degree of HBF reduction) can all cause a reduction in HBF.

Preoperative hepatic assessment

Two indices are used to assess preoperative risk in patients with underlying advanced liver disease. The Child-Pugh score, the first scoring system used to stratify the severity of end-stage hepatic dysfunction, comprises five criteria: ascites, hepatic encephalopathy, INR (international normalized ratio), serum albumin, and bilirubin concentration. Patients are then stratified into three risk categories: A, minimal; B, moderate; C, severe.

The Model for End-stage Liver Disease (MELD) score, developed at the Mayo Clinic, uses only three laboratory values in its assessment of end-stage liver disease: INR, serum creatinine, and serum bilirubin concentration:

< ?xml:namespace prefix = "mml" />MELD = 3.78 [ln bilirubin] + 11.2 [ln INR] + 9.57 [ln creatinine] + 6.43

Patients with scores less than 10 are acceptable candidates for elective operations; in patients with scores of 10 to 20, operations are associated with increased risk; operations in patients with scores greater than 20 should be avoided unless other options have been exhausted. The MELD score is also used by the United Network for Organ Sharing (UNOS) to allocate cadaveric livers for transplantation.

Liver function tests

Preoperative assessment of liver function should not be performed routinely but, rather, should be based on the patient’s history and findings on clinical examination that indicate that the patient has an increased risk for having or actually has hepatic disease.

Albumin

Serum albumin concentration is an indirect measure of the synthetic capacity of the liver and may have a predictive value for survival in hepatic disease. Because plasma half-life is 14 to 21 days, serum albumin concentrations change slowly with decreased synthesis. Albumin binds and transports neutral and acidic drugs, hormones, and bilirubin and helps maintain plasma oncotic pressure. Causes of decreased serum albumin concentration include liver disease, decreased synthesis (malnutrition), and increased losses (e.g., nephrotic syndrome, burns, ascites, and protein-losing enteropathies). Although malnutrition and hepatic dysfunction may decrease serum albumin concentration, the most common cause of decreased serum albumin concentration is severe illness. Decreased serum albumin may increase the free fraction of protein-bound drugs and decrease the amount of drug necessary to produce a desired effect. If the dose of a drug administered is not decreased in these circumstances, undesirable effects of the drug may be more frequent or pronounced. Total body albumin can be elevated in patients with cirrhosis who have a low serum albumin level but a large amount of albumin in ascitic fluid.

Prothrombin time

The prothrombin time (PT) is the most important qualitative measure of the liver’s ability to synthesize proteins. Factor VII half-life is 6 h; therefore, an abnormal PT value may indicate acute hepatic injury. The PT measures the entire extrinsic coagulation pathway. A PT that is prolonged by more than 4 sec is associated with a poor 6-month survival in patients with hepatic disease. Other causes of an increased PT include vitamin K deficiencies (e.g., malnutrition, cystic fibrosis), drug effects, decreased plasminogen levels, fibrinolysis, and disseminated intravascular coagulation.

Bilirubin

Unconjugated (indirect) bilirubin is water insoluble, minimally excreted by the kidneys, and a neurotoxin. In the liver, unconjugated bilirubin is rapidly conjugated (direct bilirubin) and secreted in bile. Because it is water soluble, conjugated bilirubin in plasma can be cleared and secreted by the kidneys. Serum levels of conjugated bilirubin do not begin to rise until the liver has lost at least half of its excretory capacity.

Unconjugated bilirubin is produced by the breakdown of heme (hemoglobin, myoglobin, and cytochrome enzymes) and is then bound to albumin for transport to the liver, where it is conjugated via glucuronyltransferase and subsequently excreted into biliary canaliculi. Overt jaundice, which occurs with total bilirubin levels above 3 mg/dL, may be accompanied by pruritus, encephalopathy, and renal insufficiency. Hemolysis causes an increase in unconjugated bilirubin, with a decrease in hemoglobin and an increase in reticulocyte count. Gilbert syndrome is a genetic defect in the conjugation pathway of bilirubin, resulting in an increase in unconjugated bilirubin without a decrease in hemoglobin and a decrease in free haptoglobin values (haptoglobin binds unconjugated bilirubin, limiting its neurotoxicity) or an increase in reticulocyte count. Intrinsic hepatic disease is reflected by an increase in conjugated bilirubin. Frequently, elevated bilirubin postoperatively can be attributed to hemolysis.

Transaminases

Transaminases are sensitive, but not specific, indicators of hepatic dysfunction. Transaminases are released in response to acute hepatic injury. The magnitude of rise in serum concentration does not always correlate with the severity of the disease. They are helpful in testing for regression or progression of hepatic disease. Higher levels are present in acute hepatic cell death (acute viral hepatitis A and B, overdose of acetaminophen, and shock). Mild elevations are seen in fatty liver disease (alcohol, diabetes, obesity), hepatitis C, hemochromatosis, Wilson disease, α₁-antitrypsin deficiency, autoimmune hepatitis, celiac sprue, Crohn disease, and ulcerative colitis. Transaminase levels may be normal or decreased in patients who undergo gastrointestinal bypass surgery and in patients with hemochromatosis, fatty liver of obesity, or end-stage hepatic disease. Skeletal muscle injury can produce marked increases in transaminase levels.

Alkaline phosphatase

Alkaline phosphatase is present in bone, the gastrointestinal tract, pancreas, and placenta and is released from bile ducts when the ducts are obstructed (obstructive jaundice), which helps differentiate obstructive jaundice from jaundice due to parenchymal hepatic disease. An elevated alkaline phosphatase level can occur in the absence of hepatic disease (e.g., metastatic bone disease, hyperparathyroidism, rickets, osteomalacia, pregnancy, and pancreatic carcinoma). Biliary disease can be diagnosed by measuring serum levels of 5´-nucleotidase (released due to bile duct obstruction or impaired bile flow).

Gamma-glutamyltransferase

Gamma-glutamyltransferase (GGT) is principally found in the kidney, liver, and pancreas and is a very sensitive but not specific marker of liver and bile duct injury. Markedly elevated increases in GGT levels are indicative of a greater degree of liver damage. Disease of the bile ducts and liver, congestive heart failure, chronic alcohol use, and prescription and nonprescription drug use can increase GGT. For this reason, it is nonspecific and must be used with other tests and clinical findings to establish a specific diagnosis.

Summary

A liver biopsy remains the gold standard for the diagnosis, grading, and staging of liver disease. Liver function tests may be useful for the differential diagnosis of liver disease, as depicted in Table 49-1.

Table 49-1

Liver Function Tests and Differential Diagnosis

Hepatic Dysfunction	Bilirubin	Transaminase Enzymes	Alkaline Phosphatase	Causes
Prehepatic	Increased unconjugated fraction	Normal	Normal	Hemolysis Hematoma resorption Bilirubin overload from transfusion of red blood cells
Intrahepatic (hepatocellular)	Increased conjugated fraction	Markedly increased	Normal to slightly increased	Viral Drugs Sepsis Hypoxemia Cirrhosis
Posthepatic (cholestatic)	Increased conjugated fraction	Normal to slightly increased	Markedly increased	Stones Sepsis

Reprinted with permission from Marschall KE. Diseases of the liver and biliary tract. In: Hines RA, Marschall KE, eds. Stoelting’s Anesthesia and Co-Existing Disease, 5th ed. Philadelphia: Churchill Livingstone; 2008:259-278.

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