1 What is the normal physiologic function of the liver?

The human liver consists of four anatomic lobes (left, right, caudate, quadrate) and eight surgical lobes (I–VIII). The liver receives approximately 20% to 25% of the cardiac output and contains 10% to 15% of the total blood volume. The portal vein supplies 75% of the blood flow of the liver and 50% of its oxygen requirements.

Almost all plasma proteins are synthesized in the liver. These include albumin, α₁-acid glycoprotein, pseudocholinesterase, and all coagulation factors except factors III, IV, and VIII. The liver is also involved in carbohydrate, lipid, and cholesterol metabolism and bile synthesis. The liver produces 20% of the body’s heme. The liver possesses an immune function in that hepatic Kupffer cells filter splanchnic venous blood of bacteria. Last, the liver serves as the main organ of drug metabolism and detoxification. Through three hepatic reactions (phases I, II, and III), drugs are metabolized to a more water-soluble form and excreted in the urine or bile. Phase I reactions use the cytochrome P-450 family of proteins and consist of oxidation, reduction, or hydrolysis. Phase II reactions undergo conjugation with substances such as glucuronic acid and amino acids. In phase III reactions, endogenous hepatic proteins use adenosine triphosphate to excrete various substances. Within the liver, nitrogen-containing compounds are degraded to urea.

2 What is the most common cause of acute parenchymal liver disease?

Viral infection is responsible for the majority of cases of acute hepatitis. Traditionally hepatitis B (HBV) was the most common form of acute viral hepatitis. However, with the advent of the HBV vaccine, hepatitis A and C are accounting for a larger percent of cases worldwide. Epstein-Barr virus and cytomegalovirus also cause acute hepatitis. Nonviral causes include drugs and toxins. Drug-induced liver injury (DILI) can mimic acute viral hepatitis and is most commonly caused by alcohol, antibiotics, and nonsteroidal anti-inflammatory drugs. DILI causing an elevation in bilirubin carries a 10% mortality rate.

3 What is cirrhosis?

Cirrhosis, the most serious sequelae of chronic hepatitis, is characterized by diffuse death of liver cells, causing fibrous tissue formation and nodular regeneration of hepatic tissue. The consequent distortion of the hepatic circulation further propagates cellular damage and results in a progressive reduction of liver cells, which eventually manifests as impairment of liver function. Hepatic synthetic failure, indicated by a prolonged prothrombin time (PT)/international normalized ratio (INR), decrease in serum albumin levels, and impairment of detoxification mechanisms resulting in encephalopathy, is often termed end-stage liver disease (ESLD).

4 Describe the neurologic derangements in patients with cirrhosis

Central nervous system dysfunction presents as hepatic encephalopathy, ranging from confusion to coma, and may be secondary to increased dietary protein consumption or gastrointestinal (GI) bleeding. Increased ammonia levels do not correlate with the degree of encephalopathy. Treatment consists of a low protein diet, lactulose, and rifaximin. Acute fulminating liver failure may present with cerebral edema and increased intracranial pressure.

5 What pulmonary changes occur in a patient with cirrhosis?

Arterial hypoxemia with compensatory hyperventilation may be secondary to atelectasis from ascites/hydrothorax or hepatopulmonary syndrome (HPS). HPS is caused by intrapulmonary arteriovenous (AV) shunting. Portal hypertension and neovascularization are responsible for these AV shunts. The clinical features of HPS include platypnea (shortness of breath while standing) and orthodeoxia (decreased saturation when upright). They are indicative of the ventilation/perfusion mismatching.

Portal pulmonary hypertension (PPH), defined as a mean pulmonary artery pressure greater than 25 mm Hg, is seen in 2% to 4% of patients with cirrhosis. Its etiology is unclear. Severe PPH is a contraindication to liver transplantation.

6 Describe the changes in the cardiovascular system in patients with cirrhosis

As liver disease progresses, most patients develop a hyperdynamic circulatory state, characterized by a fall in total peripheral resistance and a compensatory rise in cardiac output. The circulating plasma volume increases in response to vasodilation, and peripheral blood flow is enhanced. Although total body volume is increased, cirrhotic patients possess decreased effective arterial blood volume. The AV oxygen gradient narrows as a result of increased peripheral shunting. Consequently the mixed venous oxygen saturation of blood is higher than normal. The response to vasopressors is decreased with cirrhosis.

7 What is hepatorenal syndrome? How does it differ from acute renal failure in patients with end-stage liver disease?

Both types of renal failure occur in patients with cirrhosis and are characterized by oliguria and increases in serum creatinine. The etiology in both cases is renal hypoperfusion. Differentiation is important because treatment and prognosis vary.

Hepatorenal syndrome (HRS) occurs in cirrhotic patients with portal hypertension and ascites. HRS is defined as a plasma creatinine of >1.5 mg/dl and a urine sodium <10 mmol/L in the absence of other renal disease. The etiology is thought to be renal hypoperfusion resulting from a decrease in vasodilating prostaglandins and profound splanchnic sequestration of blood. HRS exists in two forms, types I and II. Type I progresses rapidly and requires immediate dialysis and liver transplantation. Type II HRS is less severe and responsive to conservative treatments, including terlipressin and a Transhepatic Intraportal Portosystemic Shunt procedure.

Acute renal failure (ARF) is caused by decreased blood flow to the kidneys. It may be the result of hemorrhage (e.g., ruptured varices), splanchnic sequestration of blood, ascites formation, or dehydration. Restoring arterial blood volume typically corrects ARF, but it can progress to acute tubular necrosis. In acute tubular necrosis, the ability to retain sodium is lost. Urine analysis will show sodium of 50 to 70 mmol/L and frequent tubular casts.

8 Describe volume assessment and fluid management in patients with hepatorenal syndrome

Optimization of renal blood flow by correction of hypovolemia may prevent further renal injury during surgery in these patients. Volume assessment may be difficult since central venous pressures are often elevated despite relative hypovolemia from increased back pressure in the inferior vena cava from hepatic enlargement or scarring. A trial of volume expansion should be undertaken as the initial treatment of oliguria. Although immediate improvement occurs in more than one third of patients treated, HRS leads to progressive renal failure unless hepatic function improves.

9 What are the gastrointestinal and hematologic derangements that occur with cirrhosis?

GIl complications result from portal hypertension (>10 mm Hg). Portal hypertension leads to the development of portosystemic venous collaterals, including esophagogastric varices. Ruptured varices with hemorrhage account for one third of the mortality in patients with cirrhosis.

Hematologic disorders include anemia, thrombocytopenia and coagulopathy. Anemia is secondary to GI bleeding, malnutrition, and bone marrow suppression. Thrombocytopenia is caused by splenic sequestration, bone marrow depression, and immune-mediated destruction. Coagulopathy is caused by decreased synthesis of clotting factors, accelerated fibrinolysis, and disseminated intravascular coagulation.

10 Which liver function tests are used to detect hepatic cell damage?

The cytosolic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are released into the blood as a result of increased membrane permeability or cell necrosis. They tend to rise and fall in parallel, although AST is cleared more rapidly from the circulation by the reticuloendothelial system. Their levels are not affected by changes in renal or biliary function. In contrast to ALT, which is mainly confined to hepatocytes, AST is found in heart and skeletal muscle, pancreas, kidney, and red blood cells. Therefore AST lacks specificity as a single diagnostic test. ALT is more specific but less sensitive for detection of hepatic disease.

11 Describe the laboratory tests used to assess hepatic synthetic function and their limitations

All clotting factors are synthesized by the liver. Factor VIII is synthesized by hepatic endothelial sinusoidal cells. PT/INR indirectly determines the amount of clotting factors available and therefore is used to assess hepatic synthetic function. Elevation in PT/INR is not specific for liver disease and is altered, for instance, by the hemophilias and disseminated intravascular coagulation. Vitamin K deficiency resulting from malabsorption in liver disease or GI diseases and anticoagulant therapy can also prolong PT/INR. Once other disease processes have been excluded, PT/INR becomes a sensitive prognostic indicator for acute hepatocellular injury.

Albumin is synthesized in the liver and also reflects hepatic synthetic ability. However, renal and gastrointestinal losses can affect plasma levels, as can changes in vascular permeability in critically ill patients. A reduction in synthesis caused by liver disease may require 20 days to detect because of the long plasma half-life of albumin. Therefore low serum albumin levels are more useful indicators of chronic liver disease.

12 What laboratory tests are used to diagnosis cholestatic liver disease?

Alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), and 5′-nucleotidase are commonly used to assess biliary tract function. These enzymes are located in the biliary epithelial cell membranes. ALP occurs in a wide variety of tissues and is elevated in a number of conditions, including bone disease and pregnancy. The hepatic origin of an elevated ALP is often suggested by the clinical context and simultaneous elevations of GGT and 5′-nucleotidase.

13 How can laboratory results be used to stratify perioperative risk in patients with cirrhosis?

In acute liver disease, plasma transaminase concentrations often increase to 10 to 100 times normal. The higher plasma concentrations are associated with greater hepatocellular death and increased mortality. Relatively normal plasma levels can also be found in patients in the earliest and latest stages of acute liver disease, signifying massive cellular necrosis, and are associated with a very high mortality. PT/INR is usually grossly prolonged, reflecting decreased synthetic ability. Albumin levels are often normal. The mortality for intra-abdominal surgery in patients with severe acute hepatic disease approaches 100%.

Liver function tests have also been used to predict outcome following surgery in patients with chronic hepatic impairment. Child’s scoring system (Table 43-1) was originally used to stratify risk in patients undergoing portosystemic shunting procedures. Using this method, 30-day mortality rates of 10%, 14% to 31%, and 51% to 80% were identified in Child’s class A, B, and C patients, respectively, when undergoing noncardiac surgery. More recently the Model for End-Stage Liver Disease (MELD) scoring system was created as a more objective method for assessing mortality in cirrhotic patients (Table 43-2). When compared to the Child’s scoring system, the MELD is a superior predictor of perioperative risk in patients with cirrhosis. MELD scores of <10, 10 to 14, and <14 correlate well with the Child’s A, B, and C classifications.

TABLE 43-2 Model for End-Stage Liver Disease Equation

INR, International normalized ratio; MELD, Model for End-Stage Liver Disease.

14 What risk factors for liver disease can be identified by history and physical examination?

Table 43-3 lists risk factors for liver disease easily obtained in a brief medical history. Physical examination may yield stigmata of chronic liver disease, including ascites, hepatosplenomegaly, spider angiomata, caput medusae, and gynecomastia. Patients with these signs or a prior history of jaundice or liver disease should have liver function tests evaluated before surgery.

TABLE 43-3 Risk Factors for Liver Disease

15 What is jaundice?

Jaundice is a visible yellow or green discoloration, usually first observed in the sclera, caused by elevation of serum bilirubin. Levels of 2 to 2.5 mg/dl (normal 0.5 to1 mg/dl) result in jaundice. The oxidation of bilirubin to biliverdin gives the green hue often observed.

16 Distinguish between unconjugated and conjugated hyperbilirubinemia

The distinction is essential to the differential diagnosis of jaundice. Elevations in the serum unconjugated bilirubin fraction are usually related to changes in the turnover of red blood cells and their precursors. Conjugated hyperbilirubinemia always signifies dysfunction of the liver or biliary tract.

17 List the common causes of unconjugated and conjugated hyperbilirubinemia

Unconjugated hyperbilirubinemia is defined as an elevation of the total serum bilirubin of which the conjugated fraction does not exceed 15%. The causes are listed in Table 43-4.

TABLE 43-4 Causes of Unconjugated Bilirubin

Elevations of conjugated bilirubin are caused by hepatocyte dysfunction and/or intrahepatic or extrahepatic stasis. A differential diagnosis of biliary stasis is listed in Table 43-5.

TABLE 43-5 Causes of Biliary Obstruction/Stasis

18 What are the main causes of hepatocyte injury?

See Table 43-6.

TABLE 43-6 Causes of Hepatocyte Injury

19 How do inhalational anesthetic gases produce hepatic dysfunction?

Although rare, all inhalational agents can cause inflammation or death of hepatocytes by direct toxicity. Adverse reactions are caused by metabolic products of halogenated inhalational agents. Generally the degree of metabolism of the agents is halothane > sevoflurane > enflurane> isoflurane > desflurane. Halothane, the most extensively metabolized agent, is associated with mild hepatic dysfunction in up to 30% of individuals exposed and manifests as asymptomatic transient elevation of hepatic AST and ALT.

Rarely an immunologically mediated idiosyncratic reaction occurs in individuals exposed to volatile anesthetics. The formation of immune complexes is related to the extent of metabolism. As halothane has the greatest degree of metabolism associated with it, hepatitis resulting from halothane exposure is the most common. However, given that halothane use is now rare in the United States, this problem is not likely to be encountered.

20 How do inhalational agents alter hepatic blood flow?

All these agents dilate the hepatic artery and preportal blood vessels. This dilation decreases mean hepatic artery pressure and increases venous pooling in the splanchnic vessels. Portal flow decreases. Overall the result is suboptimal perfusion of the liver. However, at levels below 1 minimum alveolar concentration (MAC), isoflurane, sevoflurane, and desflurane only minimally decrease hepatic blood flow. In addition, autoregulation of the hepatic artery is abolished, and blood flow becomes pressure dependent. This is usually tolerated well in patients with normal hepatic function since metabolic demand is also decreased by these drugs. Patients with hepatic disease are more susceptible to injury secondary to preexisting impaired perfusion and therefore should be anesthetized at levels below 1 MAC.

21 What are the preoperative management goals in a patient with liver disease?

The type and severity of liver disease should be determined. Patients with acute hepatitis or Child’s type C (MELD >14) cirrhosis should have elective surgeries cancelled. A complete organ system review should be performed, specifically looking for encephalopathy, ascites, portal hypertension, and renal insufficiency. A complete laboratory evaluation should be performed, including transaminases, bilirubin, albumin, basic metabolic profile, complete blood count with platelets, and a coagulation profile. For major surgery, coagulopathy should be corrected to an INR <1.5, platelets corrected to >100 × 10⁹, and fibrinogen to >100 mg/dl. A thromboelastogram may be useful in guiding component therapy when correcting a preexisting coagulopathy.

22 What are the intraoperative management goals in a patient with liver disease?

Preservation of hepatic blood flow and existing hepatic function are key. Hypoxemia, hemorrhage, and hypotension may all reduce hepatic blood flow thus these should be avoided when possible. Drug selection and dosing should be judicious. The operating room should be warmed, and a fluid warming/rapid infusion device should be available. Regional anesthesia is a good option if coagulopathy is not present.

23 What adjustment in anesthetic medications should be made in a patient with liver disease?

The induction agents propofol, etomidate, and ketamine possess a high hepatic extraction ratio; and their pharmacokinetic profile is relatively unchanged in mild-to-moderate cirrhosis. With severe hypoalbuminemia, an exaggerated induction response can be seen with thiopental. Although pseudocholinesterase levels are decreased in liver disease, the clinical prolongation of succinylcholine is not significant. Intermediate-acting steroidal nucleus nondepolarizing muscle relaxants such as vecuronium and rocuronium display a prolonged effect in cirrhotics. Their prolonged duration is accentuated with repeated dosing. Benzyl-isoquinoline relaxants such as atracurium and cisatracurium undergo organ-independent elimination, and their duration is not affected by liver disease.

Benzodiazepines metabolized by phase I oxidative reactions such as midazolam and diazepam have a prolonged duration of action. Lorazepam, cleared by phase II glucuronidation, undergoes normal metabolism. All benzodiazepines should be dosed judiciously in patients with liver disease.

All opioids, with the exception of remifentanil, are metabolized in the liver. Morphine and meperidine have a prolonged half-life in liver disease and can precipitate hepatic encephalopathy. Fentanyl, although completely metabolized by the liver, does not have a prolonged clinical effect in cirrhosis. Therefore fentanyl and remifentanil are the opioids of choice in liver disease.