Digestion of carbohydrates

Conditions impairing dietary carbohydrate uptake include disaccharidase deficiency (acquired or congenital), pancreatic insufficiency, and membrane-associated transporter defect. Dietary carbohydrates include monosaccharides (glucose and fructose present in fruits, sweet corn, corn syrup, and honey), disaccharides (sucrose, maltose, and lactose), and the principal mammalian milk sugar. Polysaccharides, such as starch, are polymers of glucose and are abundantly present in wheat, grains, potatoes, peas, beans, and vegetables. Fiber consists of nondigestible complex polysaccharides of plant origin. This includes both water-insoluble and water-soluble fiber. The average American diet is 3:1 soluble to insoluble fiber, which may be markedly altered by the diets fed to ICU patients. Insoluble fibers affect fecal bulk while soluble fibers have viscous effects in the upper GI tract, including delayed gastric emptying, decreased postprandial glycemic response, and a constipating effect. Furthermore, undigestible fiber is now known to be an important source of nutrition for the microbiome of the gut.

In the critically ill patient and those receiving tube feedings, the mechanical impact of chewing and salivary enzymes is absent. However, the liquid or elemental nature of enteral formulas circumvents that issue. For infants, who have low levels of endogenous salivary and pancreatic amylase, receiving breast milk with mammary amylase facilitates starch digestion. Pancreatic amylase is the major enzyme of starch digestion, resulting in short oligosaccharides, maltotriose, maltose, and α-limit dextrins. The amylase concentration in the duodenum becomes limiting in cases of pancreatic insufficiency—for example, severe cystic fibrosis or major resection—when amylase levels become less than 10% of normal.

The enterocyte is incapable of absorbing carbohydrates larger than monosaccharides. Therefore, further hydrolysis to monosaccharides is performed by intestinal brush border disaccharidases. Lactase and sucrose are the most clinically relevant disaccharidases and are synthesized in the enterocyte with insertion into the apical brush border membrane. With the exception of lactase and rarely sucrase, the disaccharidases are rarely rate limiting for complete carbohydrate digestion. Deficiencies of any of the disaccharidase enzymes, either acquired or hereditary, may result in carbohydrate malabsorption. This is characterized by osmotic diarrhea with elevated fecal-reducing sugars, abdominal distension, and flatulence secondary to fermentation of undigested oligosaccharides by colonic bacteria. An example of this is congenital sucrase isomaltase deficiency, an autosomal recessive disorder that is associated with absence of sucrase and maltase.

Carbohydrates are absorbed by simple diffusion of monosaccharides or via brush border–associated transport mechanisms. Glucose, galactose, and xylitol are transported with sodium by the Na ⁺ /glucose cotransporter leading to movement of luminal sodium across the apical membrane, bringing with it glucose or galactose in a one-to-one molar ratio. Glucose-galactose malabsorption is a deficiency of this transport mechanism leading to neonatal onset of severe diarrhea. The second mechanism is a non–energy-dependent facilitated transport system for fructose. The general intestinal transport mechanisms are summarized in eTable 94.1 . The capacity to absorb fructose is limited in most humans; excess ingestion of fructose has been found to cause symptoms of carbohydrate malabsorption.

Loss of the epithelium and brush border frequently lead to symptoms of carbohydrate malabsorption. Common clinical conditions include rotoviral gastroenteritis, inflammatory bowel disease, celiac disease, sprue, ischemia/hypoxia, and bacterial overgrowth of the proximal gut as a result of either stasis or use of antacids, and malnutrition. Severe mucosal damage requires 7 to 10 days for recovery of brush border function. Several infant and enteral formulas rely on starch as a carbohydrate source to minimize reliance on lactase.

Digestion of carbohydrates is generally very efficient, ranging from 80% to 100% of absorption from starch depending on the source of the starch. Bacterial fermentation of fiber and undigested carbohydrates produces short-chain fatty acids, used as fuel by the enterocytes, as well as gaseous hydrogen and methane, contributing to the flatulence associated with increased dietary fiber and malabsorption syndromes.

Digestion of proteins

Conditions impairing dietary protein uptake include ineffective pancreatic protease secretion and abnormal epithelial transport (Hartnup disease, lysinuric protein intolerance). The GI tract processes exogenous proteins with great efficiency as well as recycling endogenous proteins such as digestive enzymes, mucus, sloughed cells, and plasma proteins that leak into the alimentary tract. The enteral processing of proteins entails a digestive and transport phase.

In the digestive phase, gastric acid denatures complex proteins, making them more susceptible to the actions of proteolytic enzymes. The chief cells of the stomach release pepsinogens that are converted to active pepsins under acidic conditions. The pepsins are endopeptidases that release relatively large peptides and are inactivated when the pH rises above 4 as the food enters the duodenum. The completeness of gastric proteolysis depends in part on the rate of gastric emptying, the pH of intragastric contents, and the types of protein ingested. There is, however, no evidence that patients with achlorhydria or those receiving antacids, H ₂ blockers, or both agents have impaired protein digestion. In addition to initiating protein digestion in the mature subject, pepsins act as milk-clotting factors, which are important in the neonate for curd formation and provide bulk to the infant’s stools.

Luminal digestion proceeds in the small intestine mediated by five pancreatic peptidases that are secreted by the pancreatic acinar cells as proenzymes and activated by enterokinase and trypsin. Each peptidase possesses proteolytic activity at specific internal or external peptide bonds. Proteins are typically degraded into mixtures of one-third free amino acids and two-thirds peptides containing two to six amino acid residues, which are suitable substrates for the brush border peptidases. The brush border peptidases convert the oligopeptides into monopeptides, dipeptides, and tripeptides suitable for transport into the enterocyte.

In the transport phase, specific membrane-associated transport mechanisms exist for the uptake of amino acids and dipeptides. They involve simple diffusion , facilitated transport , and carrier-mediated active transport (see eTable 94.1 ) . Na ⁺ coupled active transport is an energy-dependent process associated with the uptake of luminal Na ⁺ and an amino acid (or glucose) and exchange of the Na ⁺ and associated molecule for potassium (K ⁺ ) through the basolateral membrane on the serosal side. Peptide transport may also occur using a hydrogen (H ⁺ )/peptide transport protein, which moves according to an H ⁺ gradient in the acidic pH microclimate of the intestinal brush border. Na ⁺ /H ⁺ exchange in the brush border and sodium-potassium adenosine triphosphatase (Na ⁺ /K ⁺ -ATPase) in the basolateral membrane maintain the necessary gradient. It is important to note that many amino acids are absorbed more rapidly as dipeptides than as free amino acids. This fact has been capitalized on in the development of enteral nutritional formulas for critically ill patients because oligopeptide mixtures have a lower osmolarity and are more efficiently absorbed than single amino acid solutions of equal nitrogen content. Because of the efficient GI absorption of dipeptides, patients with specific amino acid transport defects—for example, Hartnup disease (defective tryptophan transport) and lysinuric protein intolerance (defect in dibasic amino acid transport—lysine, arginine) infrequently have GI symptoms related to dietary protein malabsorption and instead more commonly manifest with non-GI symptoms, such as aminoaciduria.

Once inside the enterocyte, peptides are quickly degraded into their constituent amino acids by cytoplasmic peptidases. Only minute quantities of intact peptide and protein gain access to the systemic circulation. The cytoplasmic amino acids derived from digested proteins are a major source of free amino acids used directly by the enterocyte. When absorbed beyond cellular needs, the free amino acids are released to the portal venous circulation for hepatic and systemic use. Only 23% of absorbed amino acids passes to the periphery without modification. Of the remaining nitrogen, 57% is converted to urea, with the carbon skeleton salvaged for synthesizing other substances, and 20% of the total ingested amino acids are used directly for hepatic protein synthesis.

During periods of fasting, the enterocyte derives the majority of its nourishment from the mesenteric arterial vascular supply, whereas during digestion, the enterocyte derives a significant part of its nutrient requirements from the luminal contents. Experience with mucosal recovery and adaptation after injury reveals that an enteral route of nutrition permits optimal recovery. In the premature infant and neonate, the small intestine is capable of absorbing intact milk proteins by pinocytosis. These proteins may include secretory immunoglobulins from breast milk as well as food antigens. Peptidase inhibitors have been demonstrated in colostrum and breast milk, partially explaining the failure of normal digestive mechanisms to degrade some of these complex dietary proteins. Both antibodies and antigens ingested with maternal milk create an important part of the immune repertory developed during early infancy (see later section on gut immunology). Although the exact time of “closure” of the intestinal mucosa to the uptake of macromolecules has not been defined in human infants, other mammals demonstrate marked intestinal impermeability to foreign proteins by the time of weaning from breastfeeding.

Digestion of lipids

Conditions impairing dietary lipid uptake include decreased bile salt pool in the gut (biliary obstruction, short bowel syndrome), impaired pancreatic secretions (pancreatic insufficiency, pancreatitis), suboptimal gut pH (gastric hypersecretion), rapid transit time (short gut syndrome, diarrheal states), mucosal diseases (celiac disease, inflammatory bowel disease, bacterial overgrowth), and impaired enterocyte function (abetalipoproteinemia).

Dietary fat accounts for approximately 50% to 70% of the nonprotein calories consumed by infants and ≈30% of nonprotein calories consumed after age 2 years. Dietary fat is ingested principally in the form of triglycerides containing the fatty acids palmitate and oleate (C16:0 and C18:1, respectively). Dietary triglycerides of animal origin predominantly contain long-chain (i.e., longer than C14 chain length) saturated fatty acids. Polyunsaturated fatty acids are mostly of vegetable origin and include linoleic and linolenic acid, also referred to as essential fatty acids because of absent de novo synthesis in humans. Other dietary lipids include fat-soluble vitamins, cholesterol, prostaglandins, waxes, and phospholipids.

In healthy adults, digestion and absorption of fat is complete with only 5% to 7% of ingested fat escaping absorption. Under normal physiologic conditions, healthy infants up to age 9 to 12 months fail to absorb 15% to 35% of dietary fat. Digestion and absorption of dietary fat is generally completed by the middle third of the jejunum; however, the presence of dietary fiber may reduce the rate and extent of absorption. Loss of dietary fat places children at significant risk for calorie and fat-soluble vitamin malnutrition.

Regulation of electrolyte and water movement

The movement of water is primarily coupled to the movement of solute in the form of electrolytes and nutrients. It is largely passive, occurring through paracellular routes in the intestine coupled with solute movement. Expression of transporters involved in intestinal water and electrolyte transport is regionally defined in the intestines. Electrolytes are taken up by enterocytes at the apical membrane and extruded through the basolateral membrane into the paracellular space. The relatively hypertonic paracellular fluid pulls water into this space, increasing the hydrostatic pressure locally. Since the tight junction between enterocytes is more impermeable to fluid flux than the capillary membranes, fluid and electrolytes are preferentially driven in the direction of the vascular space. Tight junctions are selective and dynamic in function and are regulated by a number of signaling pathways and cellular processes that can determine the size, selectivity, and flow of molecules across this barrier.

The gut responds to both systemic and local stimuli to regulate motility, transport, and digestive functions. Secretion and motility are mediated through typical agonist membrane receptor mechanisms, by local autocrine and paracrine action, or through remote endocrine and neurocrine actions. Regulation of peristalsis is crucial for keeping the chyme in contact with the epithelial surface long enough for efficient absorption of nutrients while permitting removal of unusable material and bacteria from the alimentary tract on a regular basis. GI smooth muscle demonstrates phasic and tonic patterns of contraction. Numerous factors affecting the frequency of contractions include changes in autonomic tone, stimulation of the gut by neurohormonal peptides or pharmacologic agents, and noxious stimuli associated with infectious or inflammatory processes. Hypoxia and ischemia decrease motility, frequently leading to paralytic ileus. Neural regulation of the GI tract integrates the processes of intestinal water and electrolyte transport, motility, and blood flow. Augmentation of water and electrolyte absorption after a meal in the jejunum is neurally mediated. The enteric nervous system, capable of functioning independently, is also influenced by the autonomic nervous system.

Many other factors alter the functions of the gut. The terminal ileum and colon are particularly important in this respect. The presence of an ileostomy increases the risk of excessive sodium losses, dehydration, and electrolyte abnormalities. Terminal ileal resection or other diseases of the terminal ileum such as Crohn disease or radiation enteritis may result in bile acid malabsorption. In patients with bile acid malabsorption, bile acids reach the colon, which stimulates electrolyte and chloride secretion. Patients with mild to moderate malabsorption present with watery diarrhea and may respond to a bile acid binder such as cholestyramine. Impairment of water and ion absorption in inflammatory bowel disease may occur owing to numerous mechanisms, including alteration of epithelial integrity, augmented secretion, and reduced absorption. Intestinal inflammation is associated with defects in epithelial barrier function and has a major impact on fluid and electrolyte flux. Hyperosmolality of the ileal and colonic contents and the presence of unabsorbed bile acids in the colon lead to a diarrheal state. This state is seen when unabsorbed nutrients enter the distal alimentary tract and are broken down by enteric bacteria, resulting in increased luminal osmotic activity and osmotic diarrhea.

Electrolyte transport

Several basic mechanisms exist for the transport of electrolytes by the epithelia, as summarized in eTable 94.1 . The presence of glucose in the lumen of the small intestine stimulates increased sodium absorption through coupled transport. Backflow of sodium into the lumen is a passive process since a major task for the GI tract is sodium conservation. Systemic acidosis increases Na ⁺ and chloride (Cl ^– ) absorption in the ileum and colon, whereas alkalosis has the opposite effect. As seen in other epithelial tissues, aldosterone increases ileal and colonic absorption of Na ⁺ and can increase absorption of water in the colon three- to fourfold. Spironolactone blocks this effect. The previous enthusiastic use of glutamine in intestinal rehabilitation in the ICU has not been substantiated by recent studies. Glucocorticoids increase sodium and water absorption in the distal colon. Opiate receptor stimulation increases active Na ⁺ and Cl ^– absorption in the ileum, and opiate antagonists decrease basal absorption of water and electrolytes. The primary antidiarrheal effect of opiates, however, is mediated through a slowing of intestinal transit time.

In the colon, active absorption and secretion of K ⁺ occurs in a manner consistent with K ⁺ /H ⁺ exchange, is electroneutral, and is independent of Na ⁺ /Cl ^– exchange. The process of Na ⁺ extrusion depends on Na ⁺ /K ⁺ -ATPase pumping function located at the basolateral membranes, which may be inhibited by oxidative stress during critical illness.

Extrusion of Cl ^– follows an electrochemical potential difference. The intraluminal secretion of water and other electrolytes appears to follow active secretion of Cl ^– from the crypt cells of the jejunum, ileum, and colon, with the cystic fibrosis transmembrane conductance regulator (CFTR) mechanism playing an important role. This is a common physiologic pattern in the liver, pancreas, and kidney. Numerous substances—such as muscarinic receptor agonists, serotonin, and substance P—work through second messengers and signaling cascades to induce active Cl ^– secretion. Vasoactive intestinal peptide (VIP) mediates increased secretion of electrolytes and water by increased cyclic adenosine monophosphate production that stimulates active Cl ^– secretion and inhibits Na ⁺ -Cl ^– absorption. Certain arachidonic acid metabolites, such as prostaglandins (e.g., prostaglandin E ₁ ), increase active Cl ^– secretion with increased loss of electrolytes and fluid. Many laxatives and antacids may affect fluid and electrolyte balance by stimulating active electrolyte and fluid secretion in the terminal ileum. In addition, these agents increase mucosal permeability and stimulate motility.

Disruption of normal Na ⁺ /K ⁺ -ATPase activity results in the net secretion of fluid and electrolytes. This mechanism is the final common pathway in a number of secretory diarrheal states, such as ischemia-reperfusion, cholera, enterotoxigenic E. coli , Salmonella , Campylobacter jejuni , and Clostridium perfringens , which appear to act through second messenger pathways via their toxins. Rotavirus appears to have several mechanisms of causing diarrhea. The first appears to be a mechanism of increasing Cl ^– secretion with a resulting secretory diarrhea mediated by calcium (Ca ²⁺ ), a different mechanism than bacteria-mediated diarrheal diseases. The second is an osmotic diarrhea caused by villus destruction and resultant malabsorption. In addition, the effects of various paracrine and endocrine mediators alter intestinal adenyl cyclase activity, leading to changes in electrolyte and water balance.

Gastric acid

Hydrochloric acid secretion by the gastric parietal cell is necessary for pepsinogen activation (pH <5.0) and to reduce bacterial colonization. H ⁺ and HCO ₃ ^– are produced from water and carbon dioxide by the action of carbonic anhydrase within the parietal cell. HCO ₃ ^– is secreted into the bloodstream in exchange for Cl ^– at the basolateral membrane. Cl ^– and K ⁺ are both secreted along with H ⁺ across the apical membrane against a large concentration gradient. This is an active process, mainly due to the action of the proton pump, H ⁺ /K ⁺ -ATPase, which is the final step in gastric acid secretion and the site of action of proton pump inhibitor (PPI) antacids.

Histamine, gastrin, and acetylcholine are the main stimuli for gastric acid secretion. Gastric distension, dietary amino acids, and amines stimulate gastrin hormone secretion by G-cells located in the gastric antrum. Gastrin is the most potent endogenous stimulant of gastric acid secretion and stimulates release of histamine by the enterochromaffin-like cells. Histamine then binds to histamine-2 (H ₂ ) receptors on parietal cells, leading to acid secretion. Prostaglandins and somatostatin have an inhibitory effect on gastric acid secretion via specific receptors located on the parietal cell.

H ₂ -receptor antagonists (H2RAs) block histamine-mediated gastric acid secretion found in postprandial acid secretion, Zollinger-Ellison syndrome, and other disorders associated with hypergastrinemia. PPIs block gastric acid secretion by inhibiting the parietal cell H ⁺ /K ⁺ -ATPase. They bind irreversibly to the enzyme and subsequent secretion of acid can occur only with the synthesis of new proton pump enzyme, a process that takes 12 to 24 hours. For these reasons, PPIs have revolutionized gastric acid suppression therapy. H ₂ RAs and PPIs are equally effective in many patients for preventing bleeding in the upper part of the GI tract in patients receiving mechanical ventilation. Studies have shown that some oral PPIs suppress acid in ICU patients to a greater extent than IV PPIs. ICU patients at risk of stress ulcer–related bleeding are most likely to benefit from prophylaxis, although the increased presence of gram-negative organisms in the upper GI tract due to acid-suppressing therapies has been implicated in ventilator-associated pneumonias.

Intestinal motility

The intestines are sometimes referred to as the second brain in the body owing to the intricate neural network that allows for coordinated peristalsis, creation of suitable neurohumoral reflexes to induce digestive enzyme secretion, mixing of luminal contents to enhance absorption, and elimination of debris. The enteric nervous system is contained in the intestinal wall and consists of sensory and motor neurons as well as interneurons that coordinate activity through similar mechanisms and neurotransmitters found in the central nervous system. The enteric nervous system can function autonomously but receives significant modulating input from the sympathetic and parasympathetic nervous system. Pain receptors generally respond to stretch as occurs when pressure builds up within the lumen.

Chronic inflammatory stimulation, as seen in inflammatory bowel disease or graft-versus-host disease of the gut, may lead to central sensitization and chronic intestinal pain and spasm.

Dysmotility is commonly seen in critically ill patients due to intestinal ischemia and drug effects. The intensivist will often be confronted with the temporary inability to use the gut for nutrition or medication administration. However, in a small number of pediatric patients, many of whom have chronic neurodevelopmental disability or central nervous system dysfunction, intestinal pseudo-obstruction may develop and become permanent. ^, While acquired intestinal failure due to dysmotility is rare, it represents a major ethical dilemma, because long-term total parenteral nutrition is often the only solution to preserve life in a patient whose quality of life may be limited.

Pancreatic exocrine secretory function

The functional unit of the exocrine pancreas is the acinus, composed of specialized cells containing secretory granules that drain into ductules leading to the pancreatic duct. In contrast to the pancreatic endocrine cells that demonstrate specialized function, each acinar cell is capable of secreting all pancreatic digestive enzymes. The basolateral membrane has receptors for hormones and neurotransmitters that stimulate pancreatic secretion of the digestive enzymes stored in zymogen granules near the apical membrane of each acinar cell. Ultimately, the pancreatic duct joins with the common bile duct and drains into the duodenum through the ampulla of Vater. Anatomic variation exists such that 74% of people have a common channel, while 19% have a separate opening.

Pancreatic juice is an isotonic fluid, containing primarily Na ⁺ , K ⁺ , Cl ^– , and HCO ₃ ^– . The total volume of secretion is 2.5 L daily. CFTR is the main channel for Cl ^– secretion in the pancreas and is involved in other ion transport, which has relevance in patients with cystic fibrosis. Secretion of HCO ₃ ^– and water is mediated through the actions of the gut hormones secretin, cholecystokinin, and VIP. Stimulation of the vagus nerves or the administration of acetylcholine induces digestive enzyme secretion. These effects may be blocked with atropine.

There are four phases of pancreatic secretion. Basal secretion represents approximately 2% of the potential maximum HCO ₃ ^– _. The cephalic phase is mediated by the vagal nerves in response to the sight and smell of food. The gastric phase consists of secretion of a protein-rich pancreatic juice of low volume and HCO ₃ ^– occurs following either distention of the stomach or after the ingestion of food. The intestinal phase is characterized by marked output of digestive enzymes, fluid, and HCO ₃ ^– . ^,

The presence of HCO ₃ ^– is essential to achieve an optimal pH (pH >5) for pancreatic digestive enzyme activity and to ensure solubility of bile salts. In addition to HCO ₃ ^– , the primary secretory products of the exocrine pancreas are amylase, lipase, and the proteases. The secondary digestive enzymes consist of nucleases, colipase, and lecithinase. Cholecystokinin (CCK) is the major humoral mediator of meal-stimulated enzyme secretion. It is released from the small intestinal mucosa in response to presence of fat, protein, and starch, related to total load rather than luminal concentration. CCK activates afferent neurons in duodenal mucosa, which leads to secretin release via a vasovagal reflex. Inhibitors of exocrine pancreatic secretion include somatostatin, pancreatic polypeptide, and peptide YY. Octreotide, a somatostatin analog, has been used for its antisecretory effect in clinical management of pancreatic pseudocysts and fistulae, but its use in acute or chronic pancreatitis remains controversial. It is commonly used for chylous pleural effusions and upper GI bleeding. Inflammation of the pancreas (acute pancreatitis) both from infectious and noninfectious causes can produce a dramatic systemic inflammatory response resulting in generalized permeability changes and acute lung injury.

Examination

A complete physical examination of all children admitted to an ICU should include inspection, palpation, and auscultation of the abdomen, with particular attention to hepatic or splenic enlargement, distended superficial veins, and abdominal masses; the characteristics of the bowel sounds; and, finally, visual inspection of the perianal region for signs of trauma, fistulae, and venous distension.

Palpation of the liver provides information about the hepatobiliary tract as well as function of the right side of the heart. Normally, the liver is palpable approximately 1 to 3 cm below the right costal margin in the midclavicular line. However, assessment of liver span , and not palpation alone, is the only reliable nonradiologic method for determining liver size. Liver span is determined by percussion, palpation, and auscultation along the right midclavicular line with the patient supine and breathing quietly. The dullness of the upper border is determined by percussion. Palpation or auscultation is most commonly used to establish the lower border. The liver span increases with body weight and age in both sexes, ranging from 4.5 to 5.0 cm at 1 week of age to 7 to 8 cm in boys and 6.0 to 6.5 cm in girls by age 12 years.

Examination of the liver and abdomen should note consistency, contour, tenderness, the presence of any masses or bruits, and assessment of spleen size. Splenomegaly is denoted as a spleen that is palpable more than 2 cm below the costal margin. Documentation of the presence of ascites and stigmata of chronic liver disease is important. Ascites may be suggested by a history of recent increases in weight, on physical examination by shifting dullness or fluid wave, or by abdominal imaging—ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Tenderness over the liver suggests inflammation or stretching of the fibrous capsule through rapid enlargement. Conditions associated with downward displacement of a normal liver include hyperinflated lungs, pneumothorax, retroperitoneal masses, and subdiaphragmatic abscess. End-stage liver disease and cirrhosis are associated with a reduced liver span corresponding to decreased hepatic cell mass. The spleen tip may be palpable normally in children, especially during inspiration. However, enlargement of the spleen generally represents elevated portal venous pressures or invasive processes such as sequestration, malignancy, extramedullary hematopoiesis, or hyperplasia of the reticuloendothelial system.

Anatomy, structure, and function

The liver is the largest organ in the body. It is composed of 60% hepatocytes, approximately 17% to 20% endothelial cells and Kupffer cells (reticuloendothelial cells), 3% to 5% bile ducts, and 1% hepatic stellate cells (HSCs) and oval cells. The liver has a dual vascular supply derived from the hepatic artery branches of the celiac axis, providing about 30% of the blood supply, and the portal vein, providing approximately 70%. Innervation of the liver is by the parasympathetic branches derived from both vagi and sympathetic branches, which also carry afferent fibers derived from thoracic segments. Denervation of the liver, such as seen after liver transplantation, does not affect function.

The liver lobule, the functional unit of the liver, is composed of interconnected hepatocytes (hepatic plates) 1 to 2 cells thick and 20 to 25 cells in length separated by a venous sinusoidal space and radiating around the central vein like spokes in wheel. The narrow tissue space between the endothelial cells and hepatic plates, the space of Disse, connects with lymphatic vessels in the interlobular septa. Hepatic sinusoidal endothelial cells are flat cells that do not form intracellular junctions and overlap one another. They are fenestrated, allowing plasma to enter into the space of Disse and come into direct contact with the surface of hepatocytes. This facilitates bidirectional exchange between the hepatocytes and sinusoidal space. Macrophage-derived Kupffer cells line the sinusoidal space. These cells have a phagocytic function and contribute to the hepatic inflammatory response. Kupffer cells influence hepatocyte responses through paracrine effects following activation.

HSCs, also known as ito cells , lie within the space of Disse. HSCs serve as the hepatic storage site of vitamin A, are effectors of fibrogenesis, and play a role in extracellular matrix remodeling during recovery from injury. Chronic activation and proliferation of HSCs may lead to noncirrhotic portal hypertension, fibrosis, and cirrhosis. Bile canaliculi lie between adjacent hepatocytes and drain into small terminal bile ducts, which successively drain into larger bile ductules, intralobular bile ducts, and, eventually, the extrahepatic bile ducts. Tight junctions between the hepatocytes at the canalicular space permit unidirectional transport of substances from the hepatocytes into the canalicular space. Several different carriers, receptors, and transport proteins facilitate movement of compounds across the sinusoidal, hepatocyte, and canalicular membranes. Alkaline phosphatase, leucine aminopeptidase, and γ-glutamyl transpeptidase are transaminase enzymes selectively localized in the bile canaliculi that are released with injury and serve as markers of biliary disease ( eTable 94.2 ).

eTABLE 94.2

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