Liver and Gastrointestinal Physiology

31 

Liver and Gastrointestinal Physiology RANDOLPH H. STEADMAN, MICHELLE BRAUNFELD, AND HAHNNAH PARK

CHAPTER OUTLINE Liver Anatomy Blood Supply Liver Function Storage Filtering and Cleansing Metabolism of Nutrients Synthesis of Coagulation Factors Bile Secretion Bilirubin and Jaundice Liver Regeneration Portal Hypertension Hepatic Drug Metabolism and Excretion Anesthetic Pharmacology and the Liver Liver Disease: Etiologies and Severity Cirrhosis and Perioperative Risk: Nonhepatic Surgery Hepatic Surgery Gastrointestinal Tract Anatomy Properties of the Gastrointestinal Tract Respiration and Pharyngeal Swallowing Lower Esophageal Sphincter Neural Control Enteric Nervous System Parasympathetic Stimulation Sympathetic Stimulation Hormonal Control Splanchnic Circulation Stomach Emptying Enterogastric Nervous Reflex Secretory Functions Autonomic Stimulation Gastric Secretions Pancreatic Digestive Enzymes Bicarbonate Absorption of Nutrients Glucose Fats Gastrointestinal Disorders Anesthetic Pharmacology and the Gastrointestinal Tract Emerging Developments Tissue Engineering

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I

n perioperative management, the hepatic and gastrointestinal (GI) systems usually receive consideration after the cardiovascular and respiratory systems. However, potential perioperative problems such as aspiration, ileus, and nausea and vomiting are common and significant. Additionally, end-stage liver disease—often associated with multisystem organ failure—can be life threatening. It is incumbent in anesthesiology to understand the physiologic basis of these conditions to minimize associated complications and optimize patient outcomes.

Liver The liver weighs approximately 1.5 kg, or about 2% of total body weight in an adult. Functionally, the liver metabolizes carbohydrates, proteins, fats, hormones, and foreign substances. In addition, it filters and stores blood; stores vitamins, glycogen, and iron; and produces bile and blood coagulation factors.

Anatomy The functional unit of the liver is the lobule, or liver acinus, a structure roughly 1 × 2 mm that consists of plates of hepatocytes located in a radial distribution about a central vein (Fig. 31.1). Bile canaliculi are located between the plates and collect bile formed in the hepatocytes. The canaliculi drain into bile ducts located at the periphery of the lobule next to portal venules and hepatic arterioles. The bile ducts join to form the common hepatic duct. The cystic duct from the gallbladder and the pancreatic duct join the common hepatic duct before entering the duodenum. The sphincter of Oddi controls the flow of bile into the small intestine.1,2 Portal venules empty blood from the GI tract into the hepatic sinusoids, the space between the plates of hepatocytes that serve as the capillaries of the liver. Hepatic arterioles supply welloxygenated blood to the septa located between the plates of hepatocytes and the sinusoids. The liver typically contains between 50,000 and 100,000 lobules. The large pores of endothelium lining the sinusoids allow plasma and its proteins to move readily into the tissue spaces surrounding hepatocytes, an area known as the space of Disse, or perisinusoidal spaces. This fluid drains into the lymphatic system. The liver is responsible for generating about half of the lymph. Macroscopically the liver is divided unequally into right and left lobes by the falciform ligament (Fig. 31.2A). More recently a segmental, or surgical, anatomy has been described, known as the

CHAPTER 31  Liver and Gastrointestinal Physiology



Diaphragm (pulled up)

Sinusoids Space of Disse Terminal lymphatics

Central vein

Liver cell plate

631

Left triangular ligament

Coronary ligament

Right triangular ligament Left lobe

Kupffer cell Bile canaliculi

Right lobe

Portal vein Gallbladder (fundus)

Hepatic artery Lymphatic duct Bile duct

Round ligament (ligamentum teres)

A

Falciform ligament

Extended right hepatectomy (right trisegmentectomy) Right hepatectomy

• Fig. 31.1

  The structure of the liver lobule, or acinus. Hepatocytes radiate outward from the central vein. Blood enters the lobule from the periphery via the portal vein and hepatic artery and then flows by the plates of hepatocytes before entering the central vein. Bile flows in the opposite direction.

Left lateral Left medial section section Middle hepatic vein Left hepatic vein

Right posterior Right anterior section section Right hepatic vein

II

VII

Couinaud classification. The liver is divided into eight segments based on the anatomy of the portal and hepatic veins (Fig. 31.2B).

VIII

IVa

I

III

Blood Supply The liver receives almost 25% of cardiac output via a dual supply. The portal venules conduct blood from the portal vein that drains the GI tract. The portal vein supplies 75% of liver blood flow, about 1 L/min. The hepatic arterioles supply 25% of blood flow. Each system contributes about 50% of hepatic oxygen supply (Fig. 31.3). The high hepatic blood flow is due to low vascular resistance in the portal vein. The average portal vein pressure is 9 mm Hg, whereas hepatic venous pressure averages 0 mm Hg for a 9-mm Hg perfusion pressure gradient. However, when hepatocytes are injured and replaced by fibrous tissues, blood flow is impeded, resulting in portal hypertension, the hallmark of cirrhosis. Sinusoidal pressures greater than 5 mm Hg are abnormal and define portal hypertension (see later text).3 Sympathetic innervation from T3 to T11 controls resistance in the hepatic venules. Changes in compliance in the hepatic venous system help regulate cardiac output and blood volume. In the presence of reduced portal venous flow, the hepatic artery can increase flow by as much as 100% to maintain hepatic oxygen delivery. The reciprocal relationship between flow in the two afferent vessels is termed the hepatic arterial buffer response.4 The microcirculation of the liver lobule is divided into three zones that receive varying oxygen content.5 Zone 1 receives oxygenrich blood from the adjacent portal vein and hepatic artery. As blood moves through the sinusoid, it passes from the intermediate zone 2 into zone 3, which surrounds the central vein. Zone 3 receives blood that has passed through zones 1 and 2, reducing the oxygen content. Pericentral hepatocytes have a greater quantity of cytochrome P450 (CYP) enzymes and are the site of anaerobic metabolism. Hypoxia and reactive metabolic intermediates from biotransformation affect this zone more prominently than other zones.

IVb VI

Umbilical vein (remnant)

V

Hepatic duct Inferior vena cava Hepatic artery Portal vein Gallbladder Cystic Bile duct duct Left hepatectomy

B

Extended left hepatectomy (left trisegmentectomy)

• Fig. 31.2  Liver anatomy. A, Surface anatomy of the liver depicting the right and left lobes, separated by the falciform ligament. B, The Couinaud segments of the liver and the accompanying vascular structures. The segments resected during various partial hepatectomies are illustrated. Volatile anesthetics decrease hepatic blood flow; however, newer agents (isoflurane, desflurane, and sevoflurane) reduce flow less than older agents such as halothane.6,7

Liver Function Storage Owing to its ability to distend, the liver is capable of storing up to 1 L of blood. Thus the liver serves as a reservoir capable of accepting blood, as in the presence of heart failure, or releasing blood at times of low blood volume. The liver also stores vitamins, particularly vitamins B12 (1-year supply), D (3-month supply), and A (10-month supply). Excess body iron is transported via

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Hepatic sinuses

Hepatic vein

Inferior vena Hepatic cava artery

Aorta

Portal vein

Splenic vein Superior mesenteric vein

Intestinal vein

Intestinal artery

Spleen

Capillary

• Fig. 31.3

 

The splanchnic circulation.

apoferritin to the liver for storage as ferritin, which is released when circulating iron levels are low. Thus the liver apoferritin system serves for iron storage and as a blood iron buffer.

Filtering and Cleansing Kupffer cells, a type of reticuloendothelial cell, line the venous sinusoids. Kupffer cells are macrophages that phagocytize bacteria that enter the sinusoids from the intestines. Less than 1% of bacteria that enter the liver pass through to the systemic circulation. Metabolism of Nutrients The liver is involved in energy production and storage from nutrients absorbed from the intestines. The liver helps regulate blood glucose concentrations through its glucose buffer function. This is accomplished by storing glucose as glycogen, converting other carbohydrates (principally fructose and galactose) to glucose, and synthesizing glucose from glucogenic amino acids and from glycerol derived from triglycerides (gluconeogenesis).8 In patients with altered liver function, glucose loads are poorly tolerated, and blood glucose concentration can rise severalfold higher than postprandial levels found in patients with normal hepatic function. The liver synthesizes fat, cholesterol, phospholipids, and lipoproteins. It also metabolizes fat efficiently, converting fatty acids to acetyl coenzyme A (CoA), an excellent energy source. Some of the acetyl-CoA enters the citric acid cycle to liberate energy for the liver. The liver generates more acetyl-CoA than it consumes, so it packages the excess as acetoacetic acid for use by the rest of the body via the citric acid cycle. The majority of cholesterol synthesized in the liver is converted to bile salts and secreted in the bile. The remainder is distributed to the rest of the body where it is used to form cellular membranes. Fat synthesis from protein and carbohydrates occurs almost exclusively in the liver, and the liver is responsible for most fat metabolism. The liver also plays a key role in protein metabolism. The liver synthesizes all of the plasma proteins with the exception of gamma globulins, which are formed in plasma cells. The liver is capable of forming 15 to 50 g of protein per day, an amount sufficient to

replace the body’s entire supply of proteins in several weeks. Albumin is the major protein synthesized by the liver and is the primary determinant of plasma oncotic pressure. The liver also synthesizes the nonessential amino acids from ketoacids, which it also synthesizes. The liver can deaminate amino acids, a process required before their use for energy production or conversion to carbohydrates or fats. Deamination results in the formation of ammonia, which is toxic. Intestinal bacteria are an additional source of ammonia. The liver is responsible for the removal of ammonia through the formation of urea.

Synthesis of Coagulation Factors Blood clotting factors, except factors III (tissue thromboplastin), IV (calcium), and VIII (von Willebrand factor), are synthesized in the liver. Vitamin K is required for the synthesis of the calcium ion (Ca2+)-binding proteins prothrombin (factor II) and factors VII, IX, and X (see Chapter 43). Bile Secretion Hepatocytes produce roughly 500 mL of bile daily. Between meals the high pressure in the sphincter of Oddi diverts bile to the gallbladder for storage (Fig. 31.4). The gallbladder holds 35 to 50 mL of bile in concentrated form. The presence of fat in the duodenum causes release of the hormone cholecystokinin from duodenal mucosa, which reaches the gallbladder via the circulation and stimulates gallbladder contraction. Bile contains bile salts, bilirubin, and cholesterol. Bile salts serve as a detergent, solubilizing fat into complexes called micelles, which are absorbed. Bile salts are returned to the liver via the portal vein, completing the enterohepatic circulation. Bile salts are needed for fat absorption, and cholestasis can result in steatorrhea and vitamin K deficiency.

Bilirubin and Jaundice Bilirubin is the major end product of hemoglobin breakdown, which occurs when red blood cells reach the end of their 120-day life span. After phagocytosis by reticuloendothelial cells, hemoglobin is split into globin and heme. The heme releases iron and a fourpyrrole nucleus that forms biliverdin, which is converted to free, or unconjugated, bilirubin. Unconjugated bilirubin is conjugated in the liver, primarily with glucuronic acid, before it is secreted into bile for transport to the intestines. In the intestines, a portion of conjugated bilirubin is converted to urobilinogen by bacteria. Some urobilinogen is reabsorbed from the intestines into the blood, but most is excreted back into the intestines. A small amount is excreted into urine as urobilin. Urobilinogen that remains in the intestines is oxidized to stercobilin and excreted in feces. Jaundice is the yellow-green tint of body tissues that results from bilirubin accumulation in extracellular fluid. Skin discoloration is usually visible when plasma bilirubin reaches three times normal values. Bilirubin accumulation can occur as the result of increased breakdown of hemoglobin (hemolysis) or obstruction of bile ducts. Hemolytic jaundice is associated with an increase in unconjugated (indirect) bilirubin, whereas obstructive jaundice is associated with increases in conjugated (direct) bilirubin.9

Liver Regeneration The liver has the unique ability to restore itself after injury or partial hepatectomy. As much as two-thirds of the liver can be removed with regeneration of the remaining liver in a matter of

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Bile acids via blood stimulate parenchymal secretion of bile Secretin via blood stimulates liver ductal secretion

Vagal stimulation causes weak contraction of gallbladder

Stomach

• Fig. 31.4

 

Neural and hormonal factors that regulate bile

secretion.

Liver

Pancreas Bile stored and concentrated up to 15 times in gallbladder

Sphincter of Oddi

Duodenum

Cholecystokinin via bloodstream causes 1. Gallbladder contraction 2. Relaxation of sphincter of Oddi

Fatty food in duodenum stimulates cholecystokinin release into the bloodstream

weeks.10 Control over this process is not completely understood, but hepatocyte growth factor, produced by mesenchymal cells in the liver, is involved. Other growth factors, such as epidermal growth factor and cytokines, tumor necrosis factor, and interleukin (IL)-6 can also stimulate regeneration. The mechanism responsible for returning the liver to a quiescent state might involve transforming growth factor β, a known inhibitor of hepatocyte proliferation. The signal for cessation of regeneration appears to be related to the ratio of liver to body weight.10,11 In the presence of inflammation, as with viral hepatitis, regeneration is significantly impaired.

Portal Hypertension Ongoing inflammation results in fibrosis that constricts blood flow in the sinusoids, creating increased portal pressures. Portal hypertension is formally diagnosed by measurement of the hepatic venous gradient (HVG), defined as the difference between hepatic venous and portal venous pressures. Because direct measurement of portal venous pressures is not easily accomplished, it is estimated by the wedge pressure of the hepatic veins as measured by a balloon catheter introduced into (typically) the right hepatic vein. The difference between that wedge pressure and the free pressure in the hepatic vein is the HVG, normally 1 to 5 mm Hg. Subclinical portal hypertension appears when the HVG rises to 6 to 9 mm Hg. When HVG reaches 10 to 12 mm Hg, portal hypertension becomes a systemic condition affecting hemodynamics, fluid balance, renal function, and cognition.12 Resistance to portal blood flow causes collateral vessels to develop between portal and systemic veins. With increased pressure in the splenic vein, collateral vessels to esophageal veins develop. These

enlarge and protrude into the esophageal lumen, producing esophageal varices. Variceal size and HVG predict both the likelihood of rupture and ability to control variceal bleeding and rebleeding.13 Within 2 years of diagnosis of portal hypertension, approximately 30% of patients have a variceal hemorrhage.14 The 6-week mortality after variceal hemorrhage is 30%, which increases to 50% with a second episode of bleeding. Prophylaxis to prevent bleeding includes nonselective β blockers, long-acting nitrates, endoscopic obliteration, and endoscopic ligation.15 Portal hypertension results in portosystemic shunting. Shunted blood circumvents the filtering system of the liver. This results in the entry of drugs, ammonia, and other toxins normally handled by the liver into the systemic circulation; hepatic encephalopathy often ensues.16 Splanchnic vasodilatation reduces renal perfusion, resulting in renal failure (hepatorenal syndrome). During the early stages of acute renal injury the kidneys can be functionally normal and the changes reversible. In the absence of improvement in liver function, renal injury can become permanent.17 Systemic vasodilatation leads to hyperdynamic circulation characterized by low normal blood pressure, low systemic vascular resistance, and high cardiac output. Response to vasoconstrictors is often attenuated owing to endogenous vasodilators, an ineffective splanchnic reservoir, and increased sympathetic tone.18

Hepatic Drug Metabolism and Excretion The liver metabolizes and excretes many drugs into the bile. The liver is also responsible for metabolism of a number of hormones, including thyroxine and the steroids estrogen, cortisol, and aldosterone.

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Intrinsic hepatic clearance of a compound divided by the hepatic blood flow determines the extraction ratio. The extraction ratio indicates the efficiency with which various drugs are cleared. Efficiently extracted drugs include many opioids, β blockers (except atenolol), calcium channel blockers, and tricyclic antidepressants. Poorly extracted drugs include warfarin, aspirin, ethanol, and phenobarbital. Elimination of poorly extracted drugs is limited by intrinsic clearance and/or protein binding rather than hepatic blood flow, whereas elimination of highly extracted drugs is dependent on blood flow (see Chapter 4).

Anesthetic Pharmacology and the Liver Volatile anesthetic agents decrease hepatic blood flow. Agents currently in use—isoflurane, sevoflurane, and desflurane—affect hepatic blood flow less than older agents. Despite reductions in hepatic blood flow, liver function testing fails to show alterations of hepatic function after administration of current inhaled anesthetics.19,20 Fewer data exist on the effects of inhaled anesthetics on patients with chronic liver disease. Central neuraxial blockade decreases hepatic blood flow proportionally to the decrease in systemic blood pressure. Hepatic blood flow can be restored by administration of vasopressors. Hepatic dysfunction affects the pharmacokinetics of intravenous anesthetics through alterations in protein binding (as the result of reduced plasma proteins), increases in the volume of distribution, and reductions in hepatic metabolism.21,22 The pharmacodynamic effects of opioids and sedatives can be enhanced in patients with end-stage liver failure who have encephalopathy. Although opioids have been used successfully to treat biliary colic, they can also produce spasm of the sphincter of Oddi.23 Glucagon, opioid antagonists, nitroglycerin, and atropine reverse this effect. Intermediate-duration neuromuscular blocking agents that undergo hepatic elimination have a prolonged duration of action in the presence of liver disease. Atracurium and cisatracurium are not dependent on hepatic elimination, so dosing alterations are not required in patients with hepatic disease (see Chapter 22).

Liver Disease: Etiologies and Severity The most common causes of hepatic cirrhosis are hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. Other causes include biliary cirrhosis, autoimmune disease, hemochromatosis, drug-induced liver disease, metabolic disorders, and hepatocellular cancer.24 Biliary cirrhosis is associated with several forms of cholestatic disease, including primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. Nonalcoholic fatty liver disease (also called steatohepatitis), an increasingly recognized cause, is associated with obesity, type 2 diabetes mellitus, and the constellation of risk factors known as the metabolic syndrome.25 The severity of cirrhosis can be graded using the Child-Turcotte-Pugh (CTP) scoring system (Table 31.1).26 Patients with the most severe disease have a CTP score of 10 points or more (class C). These patients have exceedingly high perioperative mortality (up to 75%).27 Class B (7–9 points) patients also have significant perioperative mortality (30%). Preoperative risk modification, through treatment of encephalopathy and ascites, appears to reduce risk.28 An alternative mortality risk stratification for patients with liver disease undergoing nonhepatic surgery is the Model for End-Stage Liver Disease (MELD) score. The MELD score was developed to predict 90-day mortality in patients undergoing transjugular intrahepatic portosystemic shunt procedures.29 It has since been

TABLE a 31.1  Modified Child-Turcotte-Pugh Scoring System

Parameters

1 Point

2 Points

3 Points

Albumin (g/dL)

>3.5

2.8–3.5

<2.8

Prothrombin time   Seconds prolonged   International normalized ratio

<4 <1.7

4–6 1.7-2.3

>6 >2.3

Bilirubin (mg/dL)b

<2

2-3

>3

Ascites

Absent

Slight-moderate

Tense

Encephalopathy

None

Grade I-II

Grade III-IV

Class A = 5.6 points, B = 7 to 9 points, and C = 10 to 15 points. For cholestatic diseases (e.g., primarily biliary cirrhosis), the bilirubin level is disproportionate to the impairment in hepatic function and an allowance should be made. For these conditions, assign 1 point for a bilirubin level less than 4 mg/dL, 2 points for a bilirubin level of 4 to 10 mg/dL, and 3 points for a bilirubin level more than 10 mg/dL. Modified from Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646–649. a

b

validated for risk stratification of patients with liver disease in a number of different settings, including patients awaiting liver transplantation. The MELD score is used to allocate donor grafts to liver transplant candidates with the greatest urgency (highest predicted 90-day mortality).30 It is calculated as follows: MELD = 3.78 × ln bilirubin (mg/dL) + 11.2 × ln INR + 9.57 × ln creatinine (in milligrams per deciliter) + 6.43, where ln INR is the natural logarithm and INR is the international normalized ratio. In January 2016, serum sodium (Na) was added to the MELD score to account for the impact of hyponatremia on wait list mortality, particularly at lower MELD scores.31 The resulting formula is MELD-Na = MELD + 1.32 × (137 − Na) − [0.033 × MELD × (137 − Na)].32 Online calculators are convenient and commonly used to ascertain the MELD score.33

Cirrhosis and Perioperative Risk: Nonhepatic Surgery Patients with cirrhosis frequently require nonhepatic surgery for abdominal wall hernias, peptic ulcer disease, biliary, small bowel, colon and pancreatic disease, in addition to cardiac, vascular and orthopedic surgery. In the perioperative period cirrhosis can decompensate owing to the effects of surgery and anesthesia, which results in decreased hepatic blood flow and an increased risk of bacterial infection.34 Risk factors for perioperative mortality and morbidity include the severity of liver disease as determined by the CTP or MELD score, and the anatomic location of procedure, with upper abdominal surgery associated with considerable risk. A pioneering study included 140 peripheral, intraabdominal, and intrathoracic procedures in 131 patients whose MELD scores ranged from 6 to 43. Overall 30-day mortality was 16%, which correlated with MELD score and was confined to nonperipheral procedures.35 Abdominal surgery carries more risk than nonabdominal surgery owing to significant reductions in hepatic blood flow.35,36 A more recent study, which included 138 patients with cirrhosis undergoing general surgical procedures, found an overall hospital mortality of 28%. As in other series, mortality was stratified by CTP group, with mortality highest in CTP class C patients.37



Laparoscopic surgery, which is controversial because of the requirement for pneumoperitoneum, appears to reduce perioperative risk.38

Hepatic Surgery Hepatic resection surgery, most commonly for hepatocellular carcinoma and metastatic cancer, evolved over the past several decades of the 20th century. In a single-center series, the overall mortality was 4%, although subgroups with cirrhosis and biliary obstruction had higher mortality (9% and 21%, respectively).39 This improvement in survival after hepatic resection is attributed to a number of factors, including improved patient selection, volumetric studies designed to assess predicted remnant liver mass, portal vein embolization (to decrease the mass of resected tissue and stimulate regeneration of the liver remnant), and use of intraoperative ultrasound to delineate vascular anatomy and the extent of pathology.40 Additionally, the success of liver transplantation, with a 5-year patient survival of 73%, has given rise to a generation of hepatobiliary surgeons skilled in liver resection.41 Since 2000, perioperative mortality for hepatic resection has not seen further reductions, remaining at about 3%, because of expanded indications for surgery in a patient population that is older and more likely to have cirrhosis.42 Liver transplantation is recognized as definitive management for patients with acute and chronic liver failure. The liver is the second most commonly transplanted organ, after the kidney. Anesthetic management for patients undergoing liver transplantation is challenging because of unpredictable, sometimes massive, blood loss; coagulation abnormalities; electrolyte and acid-base disturbances; and hemodynamic, pulmonary, renal, neurologic, and infectious derangements.43

Gastrointestinal Tract The GI, or alimentary, tract provides the body with substrates for energy needs and essential nutrients through food digestion and absorption. Water, electrolytes, vitamins, and nutrients are supplied to the body via the exclusive function of the GI tract. Control of the process requires local, nervous system, and hormonal input.

Anatomy The anatomy of the digestive tract consists of one continuous tube connected with the external environment. It is separated into distinct sections, each adapted to specialized functions (Fig. 31.5). A typical cross section of the gut consists of multiple layers (Fig. 31.6). Moving from the outside to within, the gut is made up of the serosa, a longitudinal muscle layer, a circular muscle layer, submucosa, and mucosa. The enteric nervous system plexuses lie within the gut layers. As a barrier to the external environment, an epithelial layer lines the innermost portion of the gut.

Properties of the Gastrointestinal Tract Food moves forward in the alimentary tract by peristalsis. This movement consists of a contractile ring that encircles the gut, moving solids and liquids in front of the contractile ring forward. Peristalsis is stimulated by distention of the gut, chemical or physical irritation of the epithelial lining in the gut, and strong parasympathetic nerve signals.44 Chyme is a semifluid mixture consisting of a mixture of food and stomach secretions. In the stomach and when initially expelled from the stomach, chyme is highly acidic with a pH of around 2.

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Parotid gland Salivary glands

Mouth

Esophagus

Liver

Stomach Common bile duct Pancreas

Gallbladder Duodenum Transverse colon

Descending colon

Ascending colon

Small intestine

Appendix

Anus

• Fig. 31.5

 

The alimentary tract.

Serosa Longitudinal muscle Circular muscle Meissner’s nerve plexus Submucosa Mucossa Transverse colon Mucosal muscle Myenteric nerve plexus Submucosal gland Mesentery

• Fig. 31.6

 

A cross section of the intestines.

In the duodenum, pancreatic secretions of bicarbonate help to raise its pH (see later text).

Respiration and Pharyngeal Swallowing Swallowing occurs as a negligible interruption of about 6 seconds to the respiratory cycle. Even while talking, the act of swallowing is so rapid that it poses no threat to respiration.

Lower Esophageal Sphincter Located between the esophagus and stomach, the smooth muscle of the lower esophageal sphincter, also known as the gastroesophageal

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sphincter or cardiac sphincter, remains constricted with an intraluminal pressure of about 30 mm Hg, whereas the higher portions of the esophagus remain normally relaxed.45 Tonic constriction prevents the reflux of acidic stomach contents. Initiated by swallowing, a peristaltic wave helps coordinate the passage of food into the stomach, causing a “receptive relaxation” of the lower esophageal sphincter. Esophageal reflux is prevented by the valvelike mechanism of the distal end of the esophagus, which resists reflux of stomach contents as a result of high intraabdominal pressure. Achalasia is a disorder in which the lower esophageal sphincter loses the ability to relax in response to swallowing. The esophagus distends, which can lead to chronic regurgitation and aspiration. Another disorder that can lead to reflux is Zenker’s diverticulum, a weakness at the junction of the thyropharyngeus and cricopharyngeus muscles in the hypopharynx.

Neural Control Enteric Nervous System Important in controlling GI movement and secretion, the enteric nervous system is composed of an outer plexus (myenteric or Auerbach’s plexus) and an inner submucosal plexus (Meissner’s plexus). The outer plexus lies between the longitudinal and circular muscle layers of the gut and exerts main control over GI movements (see Fig. 31.6). The inner plexus is the main control for GI secretion and local blood flow. The myenteric plexus extends throughout the entire length of the gut as a linear chain of interconnected neurons. Lying within intestinal smooth muscle, the myenteric plexus focuses on muscle control. Upon stimulation, the plexus causes an increase in gut wall tone and in intensity of rhythmical contractions. Although it is associated mostly with excitatory muscle activity, there is also an inhibitory function of the myenteric plexus. Possibly through secretion of vasoactive intestinal polypeptide (or some other inhibitory peptide), the myenteric plexus can inhibit intestinal sphincter muscles such as the pyloric sphincter and the ileocecal valve, which normally impede the movement of gut contents.46 As a part of the inner wall, the submucosal plexus focuses on controlling local muscle intestinal secretion, local absorption, and local contraction. Parasympathetic Stimulation The cranial and sacral division of the parasympathetic system stimulates activity of the enteric nervous system. The cranial parasympathetic nerves originate almost entirely in the vagus nerves; however, some also exist at the mouth and pharyngeal regions of the tract. These nerves innervate the esophagus, stomach, pancreas, and a part of the intestines.45 The sacral parasympathetic nerves run from the second through fourth sacral segments of the spinal cord (S2-S4) and pass through to the distal half of the large intestine to end in the anus. Concerned mainly with defecation reflexes, these fibers supply the sigmoidal, rectal, and anal regions of the GI tract.47,48 Sympathetic Stimulation The sympathetic innervation of the GI tract originates in segments T5 to L2 of the spinal cord. Preganglionic fibers pass from the spinal column to the sympathetic chains. From the chains, sympathetic nerve fibers enter various outlying sympathetic ganglia such as the celiac ganglia and other mesenteric ganglia. These ganglia relay sympathetic stimulation via postganglionic fibers to

all parts of the gut by releasing mainly norepinephrine and a smaller amount of epinephrine (see Chapter 13). In contrast to the parasympathetic system, the sympathetic nervous system primarily inhibits GI tract activity. The strength of stimulation is proportional to the amount of secreted norepinephrine, which causes a range of inhibition from slight to very strong inhibition capable of causing a cessation of movement.47,48 Hence, patients undergoing emergency surgery should be considered at risk for aspiration of stomach contents.

Hormonal Control GI hormones are important for the physiologic control of gut motility. Key hormones, along with their stimuli, site of secretion, and actions, are listed in Table 31.2.

Splanchnic Circulation The blood supply of the GI system is a part of an extensive system called the splanchnic circulation. This system supplies and drains multiple organs, including the gut, spleen, pancreas, and liver. The arterial supply includes the celiac, superior mesenteric, and inferior mesenteric arteries. Venous drainage of the visceral organs occurs via the splenic, superior mesenteric, and inferior mesenteric veins. Splanchnic blood reaches the liver via the portal vein, which is a confluence of the splenic and superior mesenteric veins.

Stomach Emptying The rate of stomach emptying varies depending on the signals from the stomach and the duodenum. The duodenum is the primary regulator of the rate at which chyme enters the small intestine.

Enterogastric Nervous Reflex The enterogastric nervous reflex of the duodenum inhibits stomach emptying. Food entering the duodenum elicits various nervous reflexes that regulate the rate of stomach emptying. Factors initiating this reflex include (1) duodenal distention, (2) irritation of duodenal mucosa, (3) acidity of chyme, (4) osmolality of chyme, and (5) presence of certain breakdown products in chyme.45 Three parallel nerve circuits control stomach emptying: the gut enteric nervous system from the duodenum to the stomach; extrinsic nerves that travel to the prevertebral sympathetic ganglia and return to the stomach by the inhibitory sympathetic nerve fibers; and the vagus nerves to the brain that inhibit excitatory signals sent to the stomach. Altogether, these affect stomach emptying by inhibiting the propulsive contractions of the pyloric pump and by increasing the tone of the pyloric sphincter.49 The association between abdominal mesenteric manipulation and cardiovascular perturbations is well established.50,51 The proposed mechanism is afferent sympathetic stimulation from mesenteric traction, resulting in systemic vasodilation that provokes a compensatory increase in cardiac output.51 Although bradycardia is frequently invoked as part of this response, the change in heart rate is variable. The existence of a reflex arc has been suggested in which stimulation of the celiac plexus results in inhibition of sympathetic activity, leading to increased vagal tone and bradycardia. However, bradycardia in response to mesenteric traction has not been consistently demonstrated in controlled studies.

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TABLE 31.2  Key Gastrointestinal Hormones

Hormone

Stimuli for Secretion

Site of Secretion

Action

Gastrin

Protein Distention Nerve (Acid inhibits release)

G cells of the antrum, duodenum, and jejunum

Stimulates Gastric acid secretion Mucosal growth

Cholecystokinin

Protein Fat Acid

I cells of the duodenum, jejunum, and ileum

Stimulates Pancreatic enzyme secretion Pancreatic bicarbonate secretion Gallbladder contraction Growth of exocrine pancreas Inhibits Gastric emptying (stomach contraction) Appetite

Secretin

Acid Fat

S cells of the duodenum, jejunum, and ileum

Stimulates Pepsin secretion Pancreatic bicarbonate secretion Biliary bicarbonate secretion Growth of exocrine pancreas Inhibits Gastric acid secretion

Gastric inhibitory peptide

Protein Fat Carbohydrates

K cells of the duodenum and jejunum

Stimulates Insulin release Inhibits Gastric acids secretion Gastric motility

Motilin

Fat Acid Nerve

M cells of the duodenum and jejunum

Stimulates Gastric motility Intestinal motility

Modified1from Hall JE. Guyton and Hall Textbook of Medical Physiology. 12th ed. Philadelphia: Saunders Elsevier; 2011.

Secretory Functions The secretory function of the digestive glands is highly specialized to correspond with the food type and amount of food present in the gut. Secretions consist of digestive enzymes for the breakdown of food and mucus for the protection and lubrication of the GI tract. Estimated amounts and pH of daily secretions are listed in Table 31.3.

Autonomic Stimulation The parasympathetic nervous system stimulates an increase in alimentary glandular secretion. The glossopharyngeal and vagus parasympathetic nerves innervate glands of the upper tract; these include the salivary glands, esophageal glands, gastric glands, pancreas, and Brunner’s glands in the duodenum. Glands in the large intestine also receive parasympathetic innervation. Other glands of the gut secrete in response to local neural and hormonal stimuli rather than as a result of nerve innervation. Sympathetic stimulation to alimentary tract glandular secretion is less straightforward than parasympathetic stimulation. Sympathetic stimulation has a dual effect, causing a slight increase in glandular secretion if stimulated alone, but with preexisting parasympathetic or hormonal stimulation, sympathetic stimulation reduces secretions. This results from vasoconstriction of blood vessels that supply the glands.52

TABLE 31.3  Daily Secretion of Intestinal Juices

Daily Volume (mL)

pH

Saliva

1000

6.0–7.0

Gastric secretion

1500

1.0–3.5

Pancreatic secretion

1000

8.0–8.3

Bile

1000

7.8

Small intestine secretion

1800

7.5–8.0

Brunner’s gland secretion

200

8.0–8.9

Large intestinal secretion

200

7.5–8.0

Total

6700

Modified from Hall JE. Guyton and Hall Textbook of Medical Physiology. 12th ed. Philadelphia: Saunders Elsevier; 2011.

Gastric Secretions The stomach mucosa contains oxyntic or gastric glands and pyloric glands. Oxyntic glands secrete hydrochloric acid, pepsinogen, intrinsic factor and mucus; and pyloric glands secrete mucus and the hormone

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Vagal center of medulla Food

Cephalic phase via vagus: Parasympathetics excite pepsin and acid production

Vagus Secretory fiber trunk Afferent Local nerve plexus fibers Gastrin

Gastric phase: 1. Local nervous secretory reflexes 2. Vagal reflexes 3. Gastrin-histamine stimulation

Circulatory system

Small bowel

• Fig. 31.7

 

Intestinal phase: 1. Nervous mechanism 2. Hormonal mechanisms

Phases of gastric secretion and their regulation.

gastrin.45 The pyloric glands contain G cells (or gastrin cells) that secrete gastrin in a large form (G-34) and a smaller form (G-17) when stimulated by protein-containing foods in the antrum of the stomach. Gastrin is released into the blood and rapidly transported to the enterochromaffin-like cells of the stomach. This rapid transport is a result of the rapid mixing of gastric juices in the stomach. Histamine is also rapidly released into the deep oxyntic glands stimulating gastric hydrochloric acid secretion (Fig. 31.7).53,54

Pancreatic Digestive Enzymes The pancreas secretes enzymes that are important for the digestion of proteins, carbohydrates, and fats. For the digestion of proteins, the pancreas releases the proteases trypsin, chymotrypsin, and carboxypolypeptidase. Carboxypolypeptidase is capable of breaking down some proteins entirely to their constituent amino acids. Trypsin and chymotrypsin split proteins into smaller, various-sized peptides. Fats are digested by pancreatic lipase, cholesterol esterase, and phospholipase. Pancreatic lipase breaks down triglycerides to fatty acids and glycerol. Cholesterol esterase and phospholipase hydrolyze cholesterol esters and phospholipids, respectively. Pancreatic amylase breaks down carbohydrates (including starch and glycogen), randomly cleaving carbohydrate chains into disaccharides and trisaccharides. The proteolytic digestive enzymes released by the pancreas are inactive forms (proenzymes) when synthesized (thus preventing autodigestion of the pancreas). Release into the intestinal tract and interaction with various components of the intestinal fluid activates the enzymes by proteolytic processing. Trypsinogen can be activated by the enzyme enterokinase, which is released by the intestinal mucosa when contacted by chyme, or by previously secreted and activated trypsin (autoactivation). Bicarbonate In addition to digestive enzymes, the pancreas releases large amounts of bicarbonate that neutralize the acidity of chyme as it enters the duodenum. Pancreatic secretions also contain digestive enzymes and water. Pancreatic enzymes are secreted from the acini of the pancreatic glands, whereas bicarbonate ions and water are secreted from the epithelial cells of the ducts that lead from the acini.

Concentrations of bicarbonate can reach 145 mM, allowing neutralization of hydrochloric acid released into the stomach.55

Absorption of Nutrients Most nutrient absorption occurs in the small intestinal mucosa in the valvulae conniventes (folds of Kerckring). The stomach lacks such a highly increased surface area, allowing only the absorption of highly lipid-soluble substances, such as alcohol and aspirin, through its epithelium. Villi and the brush border of microvilli contribute to the high absorptive properties of the small intestine by adding to the total absorptive area. Daily absorption from the small intestine consists of several hundred grams of carbohydrates, 100 g or more of fat, 50 to 100 g of amino acids, 50 to 100 g of salt ions, and 7 to 8 L of water.45

Glucose Glucose is mostly absorbed by a sodium ion (Na+)-dependent glucose cotransporter mediated by a coupled secondary active transport process. This cotransporter uses an electrochemical potential difference instead of adenosine triphosphate to function. The pumping of Na+ through the basolateral membrane into the extracellular compartment by sodium-potassium adenosine triphosphatase uses adenosine triphosphate to reduce Na+ within the cell. The cotransporter allows Na+ to move down its concentration gradient into the cell from the intestinal lumen, along with a glucose molecule. After glucose enters cells, it moves by facilitated diffusion into the bloodstream. The initial active transport of Na+ out of the epithelial cell provides the electrochemical motive force for moving glucose from the intestinal lumen into the bloodstream.45 Fats Digestion of fats yields monoglycerides and fatty acids. These hydrophobic molecules travel through the alimentary tract in the form of bile micelles, which are soluble in chyme. When they reach the microvilli of the intestinal cell brush border, monoglycerides and fatty acids diffuse through the membrane into epithelial cells. Within epithelial cells, fatty acids and monoglycerides are used to synthesize new triglycerides. These triglycerides are released as chylomicrons and travel through the thoracic lymph duct to be released into the bloodstream.56

Gastrointestinal Disorders Table 31.4 lists GI and neurologic disorders, many of which have anesthetic implications. Risks from these conditions include aspiration, diabetes mellitus, malabsorption with malnutrition, and nausea/vomiting. Aspiration is a concern in patients who have eaten recently, have acid reflux disease, or have disorders of GI motility. Cricoid pressure, or the Sellick maneuver, is the posterior displacement of the cricoid cartilage, intended to close the esophagus and decrease the risk of aspiration. However, cricoid pressure lowers resting lower esophageal sphincter pressure, so the benefit is confined to the physical barrier created. Questions exist about the efficacy of the mechanical effect owing to the lateral displacement of the esophagus, which is exacerbated by posterior pressure on the cricoid cartilage. Despite little evidence supporting benefit, the use of cricoid pressure is well entrenched. Because it can worsen the view with laryngoscopy, it should be abandoned if difficulties with intubation or ventilation are encountered.57,58

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639

TABLE 31.4  Gastrointestinal Disorders

GI Disorder

Type of Disorder

Description

Cause

Abnormalities

Disorders of swallowing and of the esophagus

Myasthenia gravis or botulism

Prevents normal swallowing

Paralysis of swallowing muscles Failure of neuromuscular transmission Deep anesthesia

Achalasia

Failure of lower esophageal sphincter to relax during swallowing

Damage in neural network of myenteric plexus in lower two-thirds of esophagus

Complete abrogation of Patients under deep swallowing action anesthesia may Failure of glottis to close aspirate owing to Failure of soft palate and blocked reflex uvula to close the posterior mechanism of nares → food reflux into swallowing nose Lower esophagus remains Balloon inflated on spastically contracted the end of a Food fails to pass from swallowed esophagus to stomach esophageal tube to Prolonged constriction can stretch the blocked cause ulceration of esophagus esophageal mucosa Antispasmodic drugs to relax smooth muscle

Disorders of the stomach

Achlorhydria (and hypochlorhydria, diminished acid secretion)

When pH of gastric secretions fail to decrease below 6.5 after maximal stimulation

Failure of stomach to secrete hydrochloric acid

Pepsin also fails to be secreted, which requires acid medium for activity

Disorders of small intestine

Pancreatitis

Inflammation of pancreas; comes in form of acute pancreatitis or chronic pancreatitis

Drinking excess alcohol Blockage of the papilla of Vater by a gallstone

Sprue

Inadequate absorption of nutrients from small intestine mucosa

Nontropical sprue: (idiopathic sprue, celiac disease, gluten enteropathy) result of toxic effects of gluten

With gallstone blockage: accumulation of trypsinogen within pancreas activates trypsin and other proteolytic enzymes, causing rapid digestion and destruction of pancreas Destruction of intestinal Removal of wheat enterocytes, thus and rye flour from decreasing absorptive diet results in cure surface area within weeks

Disorders of large intestine

Gastrointestinal tract

Tropical sprue: often occurs in tropics

Possibly by inflammation of Treat with intestinal mucosa from antibacterial unidentified infectious agents agents Tremendous accumulation of Requires surgical fecal matter within colon removal of involved Failure of defecation reflexes bowel. May present and/or strong peristaltic with toxic motility megacolon Increased motility of Intravenous fluid to intestinal wall replace fluid and Increased quantity of fluid electrolytes as rapidly as lost Increased motility Excess secretion of mucus in distal colon

Megacolon (Hirschsprung disease)

Severe constipation

Lack or deficiency of ganglion cells in myenteric plexus in a segment of the sigmoid colon

Diarrhea

Rapid movement of fecal matter through large intestine

Enteritis: inflammation of intestinal tract caused by either virus or bacteria (e.g., cholera) Psychogenic diarrhea: excessive stimulation of the parasympathetic nervous system Ulcerative colitis: extensive areas of walls of large intestine become inflamed and ulcerated; cause is unknown

Chemoreceptor trigger zone

Initiation of vomiting by drugs or by motion sickness

Clinical Relation

Nervous signals arising in chemoreceptor trigger zone for vomiting Drugs (amorphine, morphine, some digitalis derivatives) Rapid change of direction or rhythm of motion of body

Repeated diarrheal bowel movements

Ileostomy to heal ulcers or Surgical removal of entire colon

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Nausea and vomiting are the most common and disturbing postoperative patient complaints, after pain. The neural pathways involved are both peripheral and central. Vagal and sympathetic afferent nerves can activate the chemoreceptor trigger zone and vomiting center, located in the medulla close to the area postrema and fourth ventricle. Neurotransmitters involved include acetylcholine, dopamine, histamine, substance P, and serotonin. The vestibular apparatus, toxic substances in the GI tract, and opioids can also provide a stimulatory effect. Clinical risk factors for postoperative nausea and vomiting include female gender, nonsmoking status, history of motion sickness, perioperative opioid use, and use of inhaled anesthetics (see Chapter 34).

Anesthetic Pharmacology and the Gastrointestinal Tract Anesthetic drugs that affect the GI tract in clinically significant ways include the depolarizing neuromuscular blocker succinylcholine, anticholinergic drugs, cholinesterase inhibitors, and opioids. Succinylcholine mimics the effect of acetylcholine at the neuromuscular junction, producing an initial muscle contraction that is clinically evident as fasciculation (see Chapter 22). Fasciculation is associated with increased intragastric pressure, potentially sufficient to overcome the lower esophageal sphincter and result in reflux of gastric contents with possible aspiration. Prevention of fasciculation with the use of a “defasciculating” or subparalytic dose of a nondepolarizing neuromuscular blocking agent might prevent or reduce the increase in intragastric pressure.59 However, that intervention is not entirely benign as it is associated with partial paralysis, aspiration, and patient complaints of difficulty breathing.60 Commonly used anticholinergic drugs include atropine, glycopyrrolate, and scopolamine. Scopolamine is used primarily for its central effects, whereas atropine and glycopyrrolate are more commonly used for their peripheral effects. Some of these uses are as antisialagogues and as antagonists of the muscarinic effects of neuromuscular blocker reversal agents (cholinesterase inhibitors), which include bradycardia, nausea, increased gastric fluid secretion, and increased GI motility (see Chapter 22). Cholinesterase inhibitors also have potentially salutary effects on the GI tract, such as increasing lower esophageal tone or treating ileus.2 Opioids are strongly associated with nausea and vomiting as the result of reducing peristaltic activity throughout the small and large intestines and increasing tone in the pyloric sphincter, ileocecal valve, and anal sphincter. Opioid-induced biliary spasm can confound diagnosis of cardiac disease and might also be misinterpreted as a biliary stone or stricture on cholangiogram. Opioids also cause pancreatic duct contraction, releasing pancreatic amylase and lipase and also potentially confounding a diagnosis of pancreatitis; however, the clinical significance of these effects has been challenged.61 Opioid-induced bowel dysfunction is a particularly troublesome complication in both surgical and medical patients because of its association with increased postoperative complications, bothersome and therapy-limiting symptoms, and hospital length of stay. Alvimopan, a peripherally acting µ-opioid receptor antagonist that does not cross the blood-brain barrier, has been shown to decrease both symptoms and hospital length of stay without compromising pain relief.62,63 Studies have documented the salutary effects of regional anesthesia and analgesia on GI motility compared with general

anesthesia for abdominal surgery.64 It is believed that a contributing factor to postoperative ileus is sympathetic stimulation caused by the surgical stress response and pain. Neuraxial regional anesthesia, which blocks afferent pain signals and efferent sympathetic outflow, can potentially minimize the depressive effects of surgery on postoperative GI motility.

Emerging Developments Tissue Engineering End-stage liver disease from any cause dramatically alters liver physiology and microanatomy. Currently the only curative therapy for end-stage liver disease is orthotopic liver transplantation. Advances in molecular biology, stem cell biology, and tissue bioengineering focused on hepatology have resulted in exciting new possibilities to repair or replace damaged liver tissue and thereby restore normal hepatic physiology. Some of these approaches are summarized in Fig. 31.8. Stem cells are at the center of this development effort. Induced pluripotent stem cells (IPSCs) are multipotential cells derived from somatic cell populations. The nucleus of a mature cell, such as a fibroblast, can be “reprogrammed” by exposure to certain transcription factors to an undifferentiated state. These IPSCs can then be directed to develop into specific cell types.65 Hepatocytes developed in this way (theoretically from the patient’s own cells) could potentially represent a source of cells for regenerative therapies (e.g., hepatocyte transplantation) or bio-artificial organ development.66,67 Most recently, a popular approach aimed toward the construction of an artificial liver involves the “decellularization” of a whole organ followed by “reseeding” with the appropriate cell types. Although in a preliminary stage, these techniques have shown promise in animal models. Similarly, automated engineering platforms emulating standard three-dimensional printer technology can be used to design and develop three-dimensional tissue configurations of various cell types, including cell structures that resemble liver tissue in terms of how the hepatocytes are organized in space relative to other cells types. These “biomanufactured” tissues have exciting potential in the quest to develop artificial “whole” livers for transplantation.66–69 Refinements in xenograft approaches are also a significant part of this hepatology research frontier. Blastocyst complementation, wherein IPSCs are used to create a chimeric animal that complements an artificially induced deficit in the recipient, is an exciting example. The result is an organ with specified genetic characteristics within an animal host. The technique has been applied successfully in animal models for the pancreas and kidney. Application to hepatology is the natural next step.66,67 Finally, the application of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]–CRISPR-associated protein [Cas]9) technology to transplant hepatology has yielded an important advance. A key limitation in creating a potentially unlimited pool of donor organs from genetically modified animals (pigs in the case of liver transplantation) has been the fear of transmitting retroviruses to humans. CRISPR-Cas9 techniques have been used to edit the porcine genome, accurately and precisely inactivating the porcine endogenous retroviruses.70 This advance eliminates a significant obstacle in development of genetically modified porcine xenotransplants for end-stage liver disease.

CHAPTER 31  Liver and Gastrointestinal Physiology



A- Liver repopulation: Challenges - Cell source - Engraftment and repopulation efficiency - Tumor potential

C- Reset of liver function: Challenges - Genetic delivery system technology - Liver diseases molecular networks

Acute liver failure and Inherent liver metabolic diseases

Healthy liver Whole liver assembly

Cirrhosis and chronic liver failure

Liver 3D organoid 3D bioprinting of liver tissue B- Liver engineering: Challenges - Cell source - Scalability of clinically relevant liver mass - Tumor potential - Improvement of biotechnology involved in organ/tissue manufacturing

• Fig. 31.8

D- Blastocyst complementation: Challenges - Xeno-immunotolerence - Xeno-zoonosis - Ethical problems - Genetic toolbox limitations

  Schematic representation of novel approaches under investigation in regenerative medicine for liver replacement and regeneration. The cell source for liver repopulation (A) and liver engineering (B) should be facilitated by an unlimited supply of induced pluripotent stem–derived hepatocytes, but the underlying tumor potential would remain to be elucidated. Successful liver repopulation will require optimizing functional hepatic cells to achieve high engraftment and repopulation efficiency. “Resetting” liver functions (C) to normal will require improvement of in vivo genetic delivery systems and better understanding of complex molecular networks associated with liver diseases. Important health and ethical issues associated with blastocyst complementation (D) will need to be addressed. The liver may contain host cells and pathogens that could pose a threat of immunologic rejection and transmission of interspecies diseases. Ethical concerns could be solved once the genetic toolbox makes it possible to restrict differentiation toward particular organs (brain and gonads). 3D, Three-dimensional. (Adapted from Collin de l’Hortet A, Takeishi K, Guzman-Lepe J, et al. Liver-regenerative transplantation: regrow and reset. Am J Transplant. 2016;16:1688–1696.)

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Key Points • The liver has a dual afferent blood supply consisting of systemic blood from the hepatic artery and portal venous blood from the splanchnic circulation. • The liver plays a key role in provision of energy requirements through the synthesis and metabolism of carbohydrates, proteins, and fats. • The liver detoxifies and transforms exogenous and endogenous compounds, including anesthetics. Altered liver function can lead to encephalopathy and alter the metabolism, volume of distribution, and protein binding of drugs. • Bile production by the liver is important in the absorption of fats. Biliary obstruction results in steatorrhea and vitamin K deficiency. • End-stage liver disease is associated with multisystem organ failure. In addition to encephalopathy, hyperdynamic changes occur in the cardiovascular system; pleural effusions and ascites reflect decreased oncotic pressure and elevated portal pressure; varices and coagulopathy lead to GI bleeding; infections occur as the result of decreased reticuloendothelial function; and renal failure can result from alterations in renal blood flow.

Key References Friedman LS. Surgery in the patient with liver disease. Trans Am Clin Climatol Assoc. 2010;121:192–205. A recent review describing liver disease-related contraindications to elective surgery. (Ref. 27). Northup PG, Wanamaker RC, Lee VD, et al. Model for End-Stage Liver Disease (MELD) predicts nontransplant surgical mortality in patients with cirrhosis. Ann Surg. 2005;242:244–251. Because of its ability to predict wait list mortality, the MELD score was adopted to allocate organs for liver transplant candidates. The authors examine the ability of the MELD score to predict survival after nontransplant surgery in patients with cirrhosis. (Ref. 35). Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology. 2008;134:1842–1860. An in-depth review of gastric acid secretion. (Ref. 53). Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology. 2007;132:1261–1269. Examines the ability of the MELD score to predict perioperative mortality in 772 cirrhotics. (Ref. 36). Ziser A, Plevak D, Wiesner R. Morbidity and mortality in cirrhotic patients undergoing anesthesia and surgery. Anesthesiology. 1999;90:42–53. Reports the effects of a number of risk factors on short- and long-term perioperative mortality of 733 patients with cirrhosis. (Ref. 28).

References 1. Bell G, Emslie-Smith D, Paterson C. Textbook of Physiology and Biochemistry. 9th ed. New York: Churchill Livingstone; 1976. 2. Stoelting R, Hillier S. Pharmacology and Physiology in Anesthesia Practice. Philadelphia: Lippincott Williams & Wilkins; 2006. 3. Shah V, Kamath P. Portal hypertension and gastrointestinal bleeding. In: Feldman M, et al, eds. Sleisinger and Fordtran’s Gastrointestinal and Liver Disease. Philadelphia: Saunders Elsevier; 2010. 4. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249(5 Pt 1):G549–G556. 5. Jones A. Anatomy of the normal liver. In: Zakim D, Boyer T, eds. Hepatology: A Textbook of Liver Disease. Philadelphia: WB Saunders; 1996.

• The GI tract is functionally divided into sections that systematically break down food to its discrete components that are absorbed and presented to the liver for storage or use. • Surgical trauma affects GI function, particularly if surgery is intraabdominal. • Anesthetic agents can affect the function of the GI tract. • Although GI dysfunction might not present a problem in the operating room, it is a contributor to perioperative morbidity in the forms of aspiration, postoperative nausea and vomiting, postoperative ileus, and delayed feeding. • Considered selection of anesthetic agents and technique can mitigate the untoward effects of anesthesia and surgery on GI function. • Although still at a preclinical stage, advances in molecular biology, stem cell biology, and tissue bioengineering focused on hepatology have resulted in exciting possibilities to repair or replace damaged liver tissue and thereby restore normal hepatic physiology.

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