HEPATIC PHYSIOLOGY & ANESTHESIA :
FUNCTIONAL ANATOMY
The liver is separated by the falciform ligament into right and left anatomic lobes; the larger right lobe has two additional smaller lobes at its posterior–inferior surface, the caudate and quadrate lobes. In contrast, surgical anatomy divides the liver based on its blood supply. Thus the right and left surgical lobes are defined by the point of bifurcation of the hepatic artery and portal vein (porta hepatis); the falciform ligament therefore divides the left surgical lobe into medial and lateral segments. Surgical anatomy defines a total of eight segments.
The liver is made up of 50,000–100,000 discrete anatomic units called lobules. Each lobule is composed of plates of hepatocytes arranged cylindrically around a centrilobular vein. Four to five portal tracts, composed of hepatic arterioles, portal venules, bile canaliculi, lymphatics, and nerves, surround each lobule.
In contrast to a lobule, an acinus, the functional unit of the liver, is defined by a portal tract in the middle and centrilobular veins at the periphery. Cells closest to the portal tract (zone 1) are well oxygenated; those closest to centrilobular veins (zone 3) receive the least oxygen and are most susceptible to injury.
Hepatic blood flow.
Bile canaliculi originate between hepatocytes within each plate and join to form bile ducts. An extensive system of lymphatic channels also forms within the plates and is in direct communication with the space of Disse.
The liver is supplied by sympathetic nerve fibers (T6–T11), parasympathetic fibers (right and left vagus), and fibers from the right phrenic nerve. Some autonomic fibers synapse first in the celiac plexus whereas others reach the liver directly via splanchnic nerves and vagal branches before forming the hepatic plexus. The majority of sensory afferent fibers travel with sympathetic fibers.
VASCULAR FUNCTIONS OF THE LIVER
Control of Hepatic Blood Flow
• Normal hepatic blood flow is about 1500 mL/min in adults, of which 25–30% is derived from the hepatic artery and 70–75% from the portal vein.
• The hepatic artery supplies 45–50% of the liver's oxygen requirements and the portal vein supplies the remaining 50–55%. The pressure within the former is arterial, whereas that in the latter is normally less than 10 mm Hg. Portal vein oxygen saturation is normally 85%. The total blood flow from this dual supply represents 25–30% of the total cardiac output.
• The hepatic artery has α1-adrenergic vasoconstricting receptors as well as β2-adrenergic, dopaminergic (D1), and cholinergic vasodilator receptors. The portal vein has only α1-adrenergic and dopaminergic (D1) receptors.
• Sympathetic activation results in vasoconstriction of the hepatic artery and mesenteric vessels, decreasing hepatic blood flow.
• β-Adrenergic stimulation vasodilates the hepatic artery; β-blockers reduce blood flow and, therefore, decrease portal pressure.
METABOLIC FUNCTIONS
The abundance of enzymatic pathways in the liver allows it to play a key role in the metabolism of carbohydrates, fats, proteins.
Carbohydrate Metabolism
• The final products of carbohydrate digestion are glucose, fructose, and galactose. With the exception of the large amount of fructose that is converted by the liver to lactate, hepatic conversion of fructose and galactose into glucose makes glucose metabolism the final common pathway for most carbohydrates.
• Most of the glucose absorbed following a meal is normally stored as glycogen. When glycogen storage capacity is exceeded, excess glucose is converted into fat.
• Only the liver and (to a lesser extent) muscle are able to store significant amounts of glycogen.
• Insulin enhances glycogen synthesis and epinephrine and glucagon enhance glycogenolysis.
• The liver and kidney are unique in their capacity to form glucose from lactate, pyruvate, amino acids (mainly alanine), and glycerol (derived from fat metabolism).
• Hepatic gluconeogenesis is vital in the maintenance of a normal blood glucose concentration.
• Glucocorticoids, catecholamines, glucagon, and thyroid hormone greatly enhance gluconeogenesis, whereas insulin inhibits it.
Fat Metabolism
• When carbohydrate stores are saturated, the liver converts the excess ingested carbohydrates (and proteins) into fat.
• To oxidize fatty acids, they are converted into acetylcoenzyme A (acetyl-CoA), which is then oxidized via the citric acid cycle to produce ATP.
• Acetyl-CoA is also used by the liver for production of cholesterol and phospholipids, which are necessary in the synthesis of cellular membranes throughout the body.
• Hepatic synthesis of lipoproteins is also important in lipid transport by blood.
Protein Metabolism
The liver performs a critical role in protein metabolism. Without this function, death usually occurs within several days.
The steps involved include (1) deamination of amino acids, (2) formation of urea (to eliminate the ammonia produced from deamination), (3) interconversions between nonessential amino acids, and (4) formation of plasma proteins.
• Deamination is necessary for conversion of excess amino acids into carbohydrates and fats.
• The ammonia formed from deamination (as well as that produced by colonic bacteria and absorbed through the gut) is highly toxic to tissues. Through a series of enzymatic steps, the liver combines two molecules of ammonia with CO2 to form urea. The urea thus formed readily diffuses out of the liver and can then be excreted by the kidneys.
• Hepatic transamination of the appropriate keto acid allows formation of nonessential amino acids and compensation for any dietary deficiency in these amino acids.
• Nearly all plasma proteins with the notable exception of immunoglobulins are formed by the liver. Quantitatively, the most important of these proteins are albumin, 1-antitrypsin, and other proteases/elastases. Qualitatively, the coagulation factors are the most important proteins.
• All coagulation factors—with the exception of factor VIII and von Willebrand factor—are produced by the liver.
• The liver also produces plasma cholinesterase (pseudocholinesterase), an enzyme that hydrolyzes esters, including some local anesthetics and succinylcholine.
• Other important proteins formed by the liver include protease inhibitors (antithrombin III, α2-antiplasmin, and α1-antitrypsin), transport proteins (transferrin, haptoglobin, and ceruloplasmin), complement, α1-acid glycoprotein, C-reactive protein, and serum amyloid A.
Drug Metabolism
• Many exogenous substances, including most drugs, undergo hepatic biotransformation.
• Hepatic biotransformations are often categorized as one of two types of reactions.
• Phase I reactions modify reactive chemical groups through mixed-function oxidases or the cytochrome P-450 enzyme systems, resulting in oxidation, reduction, deamination, sulfoxidation, dealkylation, or methylation.
• Phase II reactions, which may or may not follow a phase I reaction, involve conjugation of the substance with glucuronide, sulfate, taurine, or glycine. The conjugated compound can then be readily eliminated in urine or bile.
BILE FORMATION & EXCRETION
• Bile plays an important role in absorption of fat and in excretion of bilirubin, cholesterol, and many drugs.
• Hepatocytes continuously secrete bile salts, cholesterol, phospholipids, conjugated bilirubin, and other substances into bile canaliculi.
• Bile ducts from hepatic lobules join and eventually form the right and left hepatic ducts. These ducts, in turn, combine to form the hepatic duct, which together with the cystic duct from the gallbladder becomes the common bile duct. Biliary flow from the common bile duct into the duodenum is controlled by the sphincter of Oddi. The gallbladder serves as a reservoir for bile.
• Cholecystokinin, a hormone released by the intestinal mucosa in response to fat and protein, causes contraction of the gallbladder, relaxation of the sphincter of Oddi, and propulsion of bile into the small intestine.
Bilirubin Excretion
Bilirubin is primarily the end product of hemoglobin metabolism. It is formed from degradation of the heme ring in Kupffer cells. A much smaller amount is formed as a result of the breakdown of myoglobin and cytochrome enzymes. Heme oxygenase first breaks down hemoglobin into biliverdin, carbon monoxide, and iron; biliverdin reductase then converts the former into bilirubin. Bilirubin is then released into blood, where it readily binds to albumin. Hepatic uptake of bilirubin from the circulation is passive, but binding to intracellular proteins traps the bilirubin inside hepatocytes. Inside the hepatocyte, bilirubin is conjugated (primarily with glucuronide) and actively excreted into bile canaliculi. A small fraction of the conjugated bilirubin is reabsorbed into the bloodstream. Half the bilirubin secreted into the intestine is converted by colonic bacteria into urobilinogen. A small amount of this substance is normally reabsorbed by the intestine, only to be excreted into bile again (enterohepatic recirculation). Urobilinogen is also renally excreted to a minor extent.
LIVER TESTS
Liver abnormalities can often be divided into either parenchymal disorders or obstructive disorders based on laboratory tests. Obstructive disorders primarily affect biliary excretion of substances, whereas parenchymal disorders result in generalized hepatocellular dysfunction.
Abnormalities in Liver Tests.
Parenchymal (Hepatocellular) Dysfunction Biliary Obstruction or Cholestasis
AST (SGOT) ↑to ↑↑↑ ↑
ALT (SGPT) ↑to↑↑↑ ↑
Albumin 0 to↑↑↑ 0
Prothrombin time 0 to↑↑↑ 0 to ↑↑
Bilirubin 0 to↑↑↑ 0 to ↑↑↑
Alkaline phosphatase ↑ ↑to ↑↑↑
5'-Nucleotidase 0 to↑ ↑to ↑↑↑
γ-Glutamyl transpeptidase ↑to↑↑↑ ↑↑
Liver tests that measure hepatic synthetic function
include serum albumin, prothrombin time (PT, or international normalized ratio [INR]), cholesterol, and pseudocholinesterase.
Serum Albumin
• The normal serum albumin concentration is 3.5–5.5 g/dL.
• Albumin values less than 2.5 g/dL are generally indicative of chronic liver disease, acute stress, or severe malnutrition.
Prothrombin Time
• The PT, which is normally 11–14 s (depending on the control), measures the activity of fibrinogen, prothrombin, and factors V, VII, and X.
• Prolongations of the PT greater than 3–4 s from the control are considered significant.
• prolongation of the PT usually reflects severe liver disease unless vitamin K deficiency is present.
Liver tests that reflect hepatocellular damage
Serum Aminotransferases (Transaminases)
• These enzymes are released into the circulation as a result of hepatocellular injury or death. Two aminotransferases are most commonly measured: serum aspartate aminotransferase (AST), also known as glutamic-oxaloacetic transaminase (SGOT), and serum alanine aminotransferase (ALT), also called glutamic pyruvic-transferase (SGPT).
• AST is present in many tissues, including the liver, heart, skeletal muscle, and kidneys.
• ALT is primarily located in the liver and is more specific for hepatic dysfunction.
• Normal AST and ALT levels are below 35–45 U/L.
Blood Ammonia
• Normal whole blood ammonia levels are 47–65 mmol/L (80–110 mg/dL).
• Significant elevations of blood ammonia levels usually reflect disruption of hepatic urea synthesis.
• Marked elevations usually reflect severe hepatocellular damage.
Liver tests that reflect billiary obstruction
Serum Bilirubin
• The normal total bilirubin concentration (conjugated [direct] and unconjugated [indirect]) is less than 1.5 mg/dL (< 25 mmol/L) and reflects the balance between production and biliary excretion.
• Jaundice is usually clinically obvious when total bilirubin exceeds 3 mg/dL. A predominantly conjugated hyperbilirubinemia (> 50%) may reflect hepatocellular dysfunction, intrahepatic cholestasis, or extrahepatic biliary obstruction.
• Hyperbilirubinemia that is primarily unconjugated may be seen with hemolysis or with congenital or acquired defects in bilirubin conjugation.
Serum Alkaline Phosphatase
• Alkaline phosphatase is produced by the liver, bone, small bowel, kidneys, and placenta and is excreted into bile. Normal serum alkaline phosphatase activity is generally 25–85 IU/L in most laboratories; Most of the circulating enzyme is normally derived from bone, but with biliary obstruction more hepatic alkaline phosphatase is synthesized and released into the circulation.
• Mild elevations (up to twice normal) may be seen with hepatocellular injury or hepatic metastatic disease, higher levels are indicative of intrahepatic cholestasis or biliary obstruction.
• Electrophoretic separation allows differentiation of hepatobiliary from other isoenzymes.
• The combination of an elevated γ-glutamyl transpeptidase level together with an elevated alkaline phosphatase level strongly suggests hepatobiliary disease.
• Elevated serum γ-glutamyl transpeptidase activity is the most sensitive indicator of hepatobiliary disease.
EFFECT OF ANESTHESIA ON HEPATIC FUNCTION
Hepatic Blood Flow
• Hepatic blood flow usually decreases during regional and general anesthesia.
• Multiple factors are probably responsible, including both direct and indirect effects of anesthetic agents, the type of ventilation employed, and the type of surgery being performed.
• All volatile anesthetic agents reduce portal hepatic blood flow.
• This decrease is greatest with halothane and least with isoflurane.
• All anesthetic agents indirectly reduce hepatic blood flow in proportion to any decrease in mean arterial blood pressure or cardiac output.
• Controlled positive pressure ventilation with high mean airway pressures reduces venous return to the heart and decreases cardiac output; both mechanisms can compromise hepatic blood flow.
• Positive end-expiratory pressure (PEEP) further accentuates these effects.
• Surgical procedures near the liver can reduce hepatic blood flow up to 60%. Although the mechanisms are not clear, they most likely involve sympathetic activation, local reflexes, and direct compression of vessels in the portal and hepatic circulations.
• β-Adrenergic blockers, α1-adrenergic agonists, H2-receptor blockers, and vasopressin reduce hepatic blood flow.
• Low-dose dopamine infusions may increase liver blood flow.
Biliary Function
• All opioids can potentially cause spasm of the sphincter of Oddi and increase biliary pressure (fentanyl > morphine > meperidine > butorphanol > nalbuphine).
• Intravenous opioid administration can therefore induce biliary colic or result in false-positive cholangiograms.
• Halothane and to a lesser extent enflurane may further blunt the increase in biliary pressure following opioid administration.
• Naloxone and glucagon (1–3 mg) are also reported to relieve opioid-induced spasm.
Liver Tests
Mild postoperative liver dysfunction in healthy persons is not uncommon if sensitive tests are employed.
Persistent abnormalities in liver tests may be indicative of viral hepatitis (usually transfusion related), sepsis, idiosyncratic drug reactions, or surgical complications.
Postoperative jaundice can result from a variety of factors but the most common cause is overproduction of bilirubin because of resorption of a large hematoma or red cell breakdown following transfusion
Causes of Postoperative Jaundice.
Prehepatic (increased bilirubin production)
• Resorption of hematomas
• Hemolytic anemia transfusion
• Senescent red cell breakdown
• Hemolytic reactions
Hepatic (hepatocellular dysfunction)
• Preexisting liver disease
• Ischemic or hypoxemic injury
• Drug-induced
• Gilbert's syndrome
• Intrahepatic cholestasis
• Halothane
Posthepatic (biliary obstruction)
• Postoperative cholecystitis
• Postoperative pancreatitis
• Retained common bile duct stone
• Bile duct injury
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