Handbook of Clinical Anesthesia

Chapter 48

Hepatic Anatomy, Function and Physiology

The liver provides a diverse spectrum of vital physiologic functions and plays an essential role in maintaining perioperative homeostasis (Table 48-1) (Kaufman BS, Roccaforte JD: Hepatic anatomy, function, and physiology. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 1247–1278). Normal liver function may be present in humans when as much as 80% of the organ has been resected. Insidious hepatic diseases such as chronic hepatitis C can progress silently and destroy the majority of the liver before symptoms develop. A careful preoperative history and physical examination help identify patients in whom laboratory evaluation of liver function is appropriate. These patients are often at increased risk for perioperative morbidity and mortality, including postoperative development of overt liver dysfunction, particularly after major procedures.

  1. Hepatic Homeostasis
  2. Vascular Supply
  3. The liver receives about 25% of the cardiac output via the hepatic artery and portal vein. The hepatic artery delivers about 25% of the total hepatic blood flow but nearly 50% of the hepatic oxygen delivery. The portal vein provides the remaining 75% of total hepatic blood flow and 50% of hepatic oxygen delivery.
  4. Because portal venous blood has already perfused the preportal organs (stomach, intestines, spleen, and pancreas), it is partially deoxygenated and enriched with nutrients and other substances absorbed from the gastrointestinal tract.
  5. When patients develop portal hypertension, connections form large portosystemic shunts, permitting

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portal venous blood to return to the systemic circulation without traversing the liver (esophageal varices).

Table 48-1 Major Physiologic Functions of the Liver

Blood reservoir (the liver contains nearly 25–30 mL of blood per 100 g of tissue)
Regulator of blood coagulation (synthesis of procoagulation factors and anticoagulant factors)
Endocrine organ (synthesizes insulin-like growth factor-1, angiotensinogen, and thrombopoietin; principal site of hormone biotransformation and catabolism)
Erythrocyte breakdown and bilirubin excretion (bilirubin is an end product of heme degradation).
Metabolic functions of the liver
Carbohydrate metabolism (the liver can store a maximum of approximately 75 g of glycogen; in patients with chronic liver disease, hyperglycemia commonly occurs because portosystemic shunting allows direct entry of glucose-rich portal venous blood into the systemic circulation; hypoglycemia is a late manifestation of advanced liver disease)
Lipid metabolism (fatty acids in the liver are esterified to form triglycerides, cholesterol esters, and phospholipids)Amino acid metabolism
Synthesis of important proteins (albumin and coagulation factors and their inhibitors with the exception of factor VIII)
Immunologic function (Kupffer cells produce a variety of inflammatory mediators and cytokines)
Pharmacokinetics (by converting lipophilic substances to excretable metabolites, hepatic enzymes detoxify drugs and terminate their pharmacologic activity)

  1. Hepatic arterial pressure is similar to aortic pressure, and the mean portal vein pressure is approximately 6 to 10 mm Hg.
  2. Periportal hepatocytes located close to the terminal vascular branches of the portal vein and hepatic artery are the first to be supplied with oxygen and nutrients (zone 1). The perivenular (centrilobular) area, which is the most distant from these terminal vascular branches, has the least resistance to metabolic and anoxic damage (zone 3).
  3. Smooth endoplasmic reticulum is more abundant in these cells. Zone 3 is a primary site for glycolysis and lipogenesis. It is also the site for general

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detoxification and biotransformation of drugs, chemicals, and toxins.

  1. The anaerobic milieu of zone 3, however, is also its Achilles heel because these cells are exquisitely susceptible to injury from systemic hypoperfusion and hypoxemia. Sharply defined zone 3 necrosis is also characteristic of injury resulting from accumulation of toxic products of biotransformation as seen in toxicity from hepatotoxic drugs.
  2. Hepatic Blood Flow.Although the liver as a whole receives 25% of the cardiac output, regional blood flow within the organ is such that certain areas are highly prone to ischemia. The hepatic circulation is regulated by both intrinsic (regional microvascular) and extrinsic (neural and hormonal) mechanisms.
  3. Innervation of the Liver.The liver is predominantly innervated by two plexuses that enter at the hilum and supply both sympathetic and parasympathetic nerve fibers.
  4. Pharmacokinetics
  5. Drug metabolism is primarily a hepatic event, and the liver influences the plasma concentration of most orally and parenterally administered drugs through its synthesis of drug-binding proteins. Albumin and α1-acid glycoprotein act as sinks to decrease plasma concentrations.
  6. The goal of metabolism is to convert drugs into inactive water-soluble substances that can be excreted in the bile or urine.
  7. Patients with significant liver disease may have marked alterations of pharmacokinetics and pharmacodynamics.
  8. Portosystemic shunts allow orally administered drugs to bypass the liver.
  9. Decreases in hepatic blood flow seen in patients with liver disease may prolong the elimination half-time of high-extraction drugs.

III. Assessment of Hepatic Function

  1. Laboratory Evaluation of Hepatic Function(Table 48-2). Liver function tests (LFTs) can be classified into several broad categories.

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Table 48-2 Laboratory Evaluation of Hepatic Function

 

Bilirubin Overload (Hemolysis)

Parenchymal Dysfunction

Cholestasis

Aminotransferases

Normal

Increased (may be normal to decreased in advanced stages)

Normal (may be increased in advanced stages)

Alkaline phosphatase

Normal

Normal

Increased

Bilirubin

Unconjugated

Conjugated

Conjugated

Serum proteins

Normal

Decreased

Normal (may be decreased in advanced stages)

Prothrombin time

Normal

Prolonged (may be normal in early stages)

Normal (may be prolonged in advanced stages)

Blood urea nitrogen

Normal

Normal (may be decreased in advanced stages)

Normal

Sulfobromophthalein or indocyanine green

Normal

Retention

Normal or retention

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Table 48-3 Causes of Hyperbilirubinemia

Unconjugated (Indirect)
Excessive bilirubin production (hemolysis)
Immaturity of enzyme systems
Physiologic jaundice of newborn
Jaundice of prematurity
Inherited defects
Gilbert's disease
Crigler-Najjar syndrome
Conjugated (Direct)
Hepatocellular disease (hepatitis, cirrhosis, drugs)
Intrahepatic cholestasis (drugs, pregnancy)
Benign postoperative jaundice, sepsis
Congenital conjugated hyperbilirubinemia
Dubin-Johnson syndrome
Rotor's syndrome
Obstructive jaundice
Extrahepatic (calculus, stricture, neoplasm)
Intrahepatic (sclerosing cholangitis, neoplasm, primary biliary cirrhosis)

  1. Indices of Hepatocellular Damage.Increased serum activities of aspartate aminotransferase (AST; formerly serum glutamic oxalacetic transaminase [SGOT]) and alanine aminotransferase (ALT; formerly serum glutamic pyruvic transaminase [SGPT]) are detected when hepatocellular injury and necrosis are present.
  2. Indices of Obstructed Bile Flow.
  3. Alkaline phosphatase (AP) elevations that are disproportionate to changes in AST and ALT occur with intrahepatic or extrahepatic obstruction to bile flow. (This is a highly sensitive test for assessing the integrity of the biliary system.)
  4. Hyperbilirubinemia is classified as either predominantly unconjugated or predominantly conjugated (Table 48-3).
  5. Indices of Hepatic Synthetic Function
  6. Measurement of serum albumin level and assays of coagulation function are the most widely used methods for assessing hepatic synthetic function.
  7. Because the half-life in serum is as long as 20 days, the serum albumin level is not a reliable indicator of hepatic protein synthesis in patients with acute liver disease.

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  1. The prothrombin time (PT) and international normalized ratio (INR) are sensitive indicators of severe hepatic dysfunction whether patients have acute or chronic liver disease because of the short half-life of factor VII. A progressively increasing PT is usually ominous in patients with acute hepatocellular disease, suggesting an increased likelihood of acute hepatic failure.
  2. Indices of Hepatic Blood Flow and Metabolic Capacity
  3. Elimination of the dye indocyanine green (ICG) from the blood provides an estimate of hepatic perfusion and hepatocellular function because it is highly extracted (70% to 95% by the liver after an intravenous injection).
  4. Hepatic function can also be assessed with substances that are metabolized selectively by the liver (e.g., lidocaine is metabolized by oxidative N-demethylation to monoethylglycinexylidide [MEGX]).
  5. Hepatobiliary Imaging
  6. Ultrasonography is the primary screening test for hepatic disease, gallstones, and biliary tract disease.
  7. Computed tomography provides better and more complete anatomic definition than ultrasonography.
  8. Percutaneous transhepatic cholangiography may be used to determine the level and cause of biliary obstruction, confirm the presence of cholestasis without obstruction, and evaluate whether a proximal cholangiocarcinoma is surgically resectable.
  9. Endoscopic retrograde cholangiopancreatography (ERCP) uses endoscopy to visualize the ampulla of Vater and guide insertion of a guidewire and catheter through the ampulla to permit selective injection of contrast material into the pancreatic and common bile ducts, which are then imaged radiographically. ERCP is the imaging technique of choice in patients with choledocholithiasis because sphincterotomy and stone extraction can often be performed.
  10. Liver biopsyhas a central role in the evaluation of patients with suspected liver disease because it provides the only means of determining the precise nature of hepatic damage (necrosis, inflammation, steatosis, or fibrosis). The presence of coagulopathy (PT that is 3 seconds greater than the control or platelet count <60,000 cells/mL3)

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contraindicates percutaneous liver biopsy, although trans-jugular liver biopsy can be performed safely in these patients.

  1. Hepatic and Hepatobiliary Diseases

Liver diseases are divided into parenchymal and cholestatic diseases (Table 48-4).

  1. Cirrhosis: A Paradigm for End-Stage Parenchymal Liver Disease

(Tables 48-5, 48-6 and 48-7)

Table 48-4 Classification of Liver Disease

Parenchymal Diseases
Viral hepatitis
   Hepatitis C (accounts for 40% of chronic liver disease; because of the use of serologic testing in screening donated blood, hepatitis C has almost been eliminated as a cause of posttransfusion hepatitis)
   Cytomegalovirus
   Epstein-Barr virus
   Herpes simplex virus
Nonviral hepatitis
   Toxin and drug-induced hepatitis
      Acetaminophen
      NSAIDs
      Antibiotics
      Volatile anesthetics (metabolism to trifluoroacyl metabolites may result in cross-sensitivity between fluorinated volatile anesthetics; the exception is sevoflurane, which is not metabolized to trifluoroacyl metabolites)
      Non-opioid sedative–hypnotic agents (rare)
      Opioids (increase the tone of the common bile duct and sphincter of Oddi but are unlikely to be hepatotoxic)
Inflammation and sepsis
Hypoxia and ischemia
   Severe congestive heart failure
   Surgical stress
Chronic hepatitis
Fatty liver disease
Alcoholic liver disease
Cholestatic Diseases
Biliary obstruction

NSAID = nonsteroidal anti-inflammatory drug.

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Table 48-5 Pathophysiology of Hepatic Cirrhosis

Cardiovascular Abnormalities
Hyperdynamic circulation
Hypervolemia
Arteriovenous collateralization
Cardiomyopathy
Hepatic Circulatory Dysfunction
Portal hypertension
Ascites
Variceal hemorrhage
Sepsis and infection
Pulmonary Dysfunction
Arterial hypoxemia (intrapulmonary vascular dilations)
Hydrothorax
Portopulmonary hypertension
Ascites
Renal Dysfunction and the Hepatorenal Syndrome
Spontaneous Bacterial Peritonitis
Hematologic and Coagulation Disorders
Hyperfibrinolysis
Elevated PT and INR serve as prognostic indicators
Thrombocytopenia
Endocrine Disorders
Abnormal glucose utilization (prone to hypoglycemia)
Abnormal metabolism of sex hormones (gonadal dysfunction in both men and women)
Hepatic Encephalopathy (treatment is orthotopic liver transplantation)

INR = international normalized ratio; PT = prothrombin time.

  1. Uncommon Causes of Cirrhosis

(Table 48-8)

VII. Hepatocellular Carcinoma

  1. Primary hepatocellular carcinoma (HCC) is one of the most common tumors in the world and is the third most frequent cause of death from cancer.
  2. HCC usually arises in a cirrhotic liver. The most common presenting complaint is abdominal pain, and the most frequent finding on physical examination is an abdominal mass.

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Table 48-6 Differential Diagnosis of Acute Azotemia in Patients with Liver Disease

 

Prerenal Azotemia

Hepatorenal Syndrome

Acute Renal Failure (Acute Tubular Necrosis)

Urinary sodium concentration (mEq/L)

<10

<10

>30

Urine-to-plasma creatinine ratio

>30:1

>30:1

<20:1

Urinary osmolality

Exceeds plasma osmolality by at least 100 mOsm

Exceeds plasma by at least 100 mOsm

Equal to plasma osmolality

Urinary sediment

Normal

Unremarkable

Casts or cellular debris

Table 48-7 Modified Child-Pugh Score

 

Points*

1

2

3

Albumin (g/dL)

>3.5

2.8–3.5

<2.8

Prothrombin time

   Seconds prolonged

<4

4–6

>6

   INR

<1.7

1.7–2.3

>2.3

Bilirubin (mg/dL)

<2

2–3

>3

Ascites

Absent

Slight to moderate

Tense

Encephalopathy

None

Grades I–II

Grades III–IV

*Class A, 5 to 6 points; class B, 7 to 9 points; class C, 10 to 15 points.
INR = international normalized ratio.

Table 48-8 Uncommon Causes of Cirrhosis

Wilson's disease (characterized by hepatic copper accumulation)
Hemochromatosis (characterized by excessive iron absorption)
Primary biliary cirrhosis (positive antimitochondrial antibody test result)
α1-Antitrypsin deficiency
Budd-Chiari syndrome (venous outflow obstruction from the liver)

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VIII. Pregnancy-Related Disorders

  1. Acute fatty liver of pregnancyoccurs in the late stages of pregnancy.
  2. Affected women usually present in the third trimester with symptoms related to hepatic failure.
  3. When acute fatty liver is diagnosed, delivery of the fetus is expedited. (The disease usually improves in response to termination of pregnancy.)
  4. Preeclampsia and HELLP Syndrome(increased liver transaminases, thrombocytopenia, and hyperbilirubinemia). Prompt delivery of the fetus is indicated if the syndrome develops beyond 34 weeks of gestation or earlier if life-threatening morbidity develops in the mother.
  5. Hepatic Rupture, Hematoma, and Infarct.These conditions occur in women with preeclampsia and may be the extreme end of the spectrum of HELLP syndrome.
  6. Cholestatic Disease
  7. Cardiovascular Dysfunction.The presence of bile salts in circulating blood (cholemia) can impair myocardial contractility.
  8. Coagulation Disorders.Cholestatic disease predisposes the patient toward development of coagulopathy primarily related to vitamin K deficiency. The coagulation disorders are usually moderate, and parenteral vitamin K corrects the problem. If such patients need urgent surgery, the coagulopathy requires immediate treatment with fresh-frozen plasma.
  9. Perioperative Management

(Table 48-9)

  1. Causes of Postoperative Liver Dysfunction Unrelated to Perioperative Factors
  2. Asymptomatic and Pre-Existing Hepatic Injury.Although postoperative liver dysfunction may result from anesthetic or surgical interventions, it is often unrelated to perioperative factors (pre-existing liver disease).
  3. Congenital Disorders
  4. Gilbert's syndrome(familial unconjugated hyperbilirubinemia) is the most common cause of jaundice. It is

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a benign metabolic disorder characterized by a decrease in the activity of the hepatic enzyme bilirubin glucuronyltransferase, which is required for hepatocyte uptake of unconjugated bilirubin.

Table 48-9 Perioperative Management of Patients with Liver Disease

Preoperative
Hepatic evaluation and preparation (prior episodes of jaundice, use of alcohol, current medications, easy bruising, episodes of gastrointestinal bleeding; liver function tests should be performed only if there is a suspicion of liver dysfunction based on history and physical examination; surgical morbidity and mortality are increased; these patients are sensitive to all sedatives)
Intraoperative
Monitoring and vascular access (arterial cannula, central venous, assessment of coagulation status)
Selection of anesthetic technique (regional anesthesia for peripheral procedures without coagulation abnormalities)
Induction of general anesthesia (all IV induction drugs are acceptable; decreased cholinesterase activity because of liver disease is rarely a problem)
Maintenance of anesthesia (the adequacy of blood flow and oxygen supply to the liver should be considered; opioids are useful; clearance mechanisms of muscle relaxants should be considered)
Fluids and blood products
Vasopressors (peripheral vasodilation may be resistant to vasopressors)
Postoperative
Liver dysfunction and management (postoperative dysfunction is usually transient; jaundice is the earliest sign of significant dysfunction)
Hemolysis and transfusion (reabsorption of surgical hematomas and transfusions are sources of jaundice in the absence of hepatocellular dysfunction)

IV = intravenous.

  1. Patients with Crigler-Najjar syndrome(congenital nonhemolytic jaundice) exhibit either an absence (type 1) or marked decrease (type 2) of bilirubin glucuronyltransferase, producing unconjugated hyperbilirubinemia.
  2. Surgical and anesthesia-related problems are apparently minimal in patients with Gilbert's and Crigler-Najjar syndromes.

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XII. Conclusion: Prevention and Treatment of Postoperative Liver Dysfunction

  1. Identifying patients at high risk for developing liver dysfunction or for having an exacerbation of pre-existing liver disease is of utmost importance for minimizing the morbidity and mortality in such patients (careful preoperative evaluation).
  2. When liver abnormalities are recognized preoperatively, it is prudent to defer elective procedures until the course of the disease can be determined.
  3. For operations that cannot be deferred, clinically significant pathophysiologic changes associated with the liver disease (coagulopathy, fluid and electrolyte abnormalities) should be corrected.
  4. The choice of anesthesia is usually an insignificant issue for peripheral or minor surgery (operations that do not affect splanchnic blood flow).
  5. The selection of pharmacologic anesthetic agents may have important implications in patients undergoing major operations.
  6. A primary goal during the maintenance of anesthesia is to ensure the adequacy of splanchnic, hepatic, and renal perfusion, especially in patients with severe liver disease who undergo major abdominal operations.

Table 48-10 Causes of Postoperative Liver Dysfunction

Hepatocellular

Drugs
Anesthetics
Ischemia
Shock, hypotension, iatrogenic injury
Viral hepatitis

Cholestasis

Benign postoperative cholestasis
Sepsis
Bile duct injury
Drugs
Antibiotics, antiemetics
Choledocholithiasis or pancreatitis
Cholecystitis
Gilbert syndrome

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  1. When postoperative hepatic injury occurs, the mainstay of therapy is supportive (Table 48-10).
  2. The hepatotoxic potentials of all medications merit consideration. Any medication that is suspect should be discontinued.
  3. Extrahepatic biliary obstruction should be considered in the differential diagnosis because it may require prompt surgical intervention.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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