Gastric, intestinal, and pancreatic function

Background

The stomach, intestinal tract, and pancreas are closely related both anatomically and functionally. The clinical manifestations, such as diarrhea or malabsorption, may be associated with disease of any of these organs. It is therefore appropriate to discuss them together. Advances in imaging techniques and improvements in endoscopic procedures have led to many traditional laboratory tests of gastrointestinal (GI) and pancreatic function becoming obsolete. However, in recent years, there has been a resurgence in the role of the laboratory in the investigation of the GI tract, particularly with the development of noninvasive biomarkers of GI tract inflammation and in the detection of pancreatic insufficiency.

Content

In this chapter, the anatomy and physiology of the GI tract and the normal processes of digestion and absorption are reviewed. Disorders of the stomach, pancreas, and intestine in which the laboratory plays a role in diagnosis and monitoring are discussed. The chapter concludes with an overview of GI regulatory hormones and neuroendocrine tumors in which GI symptoms are prominent, and with sections on strategies for the investigation of malabsorption and diarrhea.

Anatomy

The GI tract is a hollow tube, approximately 8 m in length, beginning with the mouth and ending with the anus. The esophagus, which is approximately 25 cm in length, is a muscular tube connecting the pharynx to the stomach. The laboratory has little role in the investigation of disorders of the esophagus, so this chapter will focus on the stomach, intestines, and pancreas.

Stomach

The stomach consists of three major zones: the cardiac zone, the body, and the pyloric zone ( Fig. 52.1 ). The upper cardiac zone includes the fundus and contains mucus and pepsinogen II–secreting surface epithelial cells and endocrine secreting cells. The body of the stomach contains cells or cell groups of many different types: surface epithelial cells that secrete mucus; parietal cells that secrete hydrochloric acid and intrinsic factor; chief cells that secrete group I and II pepsinogens; enterochromaffin cells that secrete serotonin; and other endocrine cells. The pyloric zone is subdivided into the antrum (approximately the distal third of the stomach), the pyloric canal, and the sphincter. The cells of the pyloric zone secrete mucus, group II pepsinogens, serotonin, and gastrin, but not hydrochloric acid. In the stomach, food is converted into a semifluid, homogeneous material (chyme) that passes through the pyloric sphincter into the small intestine. The digestion of proteins begins with the action of pepsin produced in the stomach.

Pancreas

The pancreas is 12 to 15 cm long and lies across the posterior wall of the abdominal cavity. The head is located in the duodenal curve, with the body and tail extending to the left to the spleen ( Fig. 52.2 ). The pancreas secretes a juice containing digestive enzymes and bicarbonate that enters the duodenum through the ampulla of Vater and the sphincter of Oddi to mix with the bolus of food coming from the stomach.

Neurogenic phase

The neurogenic or cephalic phase is initiated by the intake of food into the mouth; the sight, smell, and taste of food stimulates the cerebral cortex and subsequently the vagal nuclei.

Processes of digestion and absorption

The total quantity of fluid absorbed each day by the gut is estimated to be approximately 9 L, which is composed of 2 L oral intake, 1.5 L saliva, 2.5 L gastric juice, 0.5 L bile, 1.5 L pancreatic juice, and 1 L intestinal secretions. More than 90% of this fluid is absorbed in the small intestine. The maximal absorptive capacity for fluid is probably at least 20 L. Typically, several hundred grams of carbohydrates, 100 g of fat, and 50 to 100 g of amino acids are absorbed daily in the small intestine, but the maximal absorptive capacity is believed to be at least 10 times higher. This considerable reserve capacity may explain the lack of symptoms from mild disease processes, at least in the early stages. The efficiency of absorption is due to the unique features of the absorptive surface of the bowel and the relationship of the epithelial cells to the underlying rich vascular plexus and lymphatic vessels.

Digestion of food starts in the mouth through the action of salivary amylase and lingual lipase, but principally takes place both within the lumen of the small intestine and at the mucosal (brush border) surface. Defects of digestion may occur at one or more stages of this process. The terms maldigestion and malabsorption refer to different functional abnormalities. Maldigestion is a dysfunction of the digestive process that may occur at various sites in the GI tract. For example, a reduction in the acidity in the stomach will reduce peptic digestion of protein, whereas hyperacidity of the duodenum (e.g., due to overproduction of gastrin by a tumor in the Zollinger-Ellison syndrome) can inactivate pancreatic enzymes. Loss of brush border enzymes in the small intestine as a result of a variety of conditions can prevent oligosaccharides and disaccharides from being further hydrolyzed. Pancreatic insufficiency will reduce intraluminal enzyme activity in the small gut, causing maldigestion of fats and proteins. Inherited disorders of the exocrine pancreas can cause pancreatic insufficiency secondary to chronic pancreatic inflammation and ultimately lead to maldigestion. In contrast, malabsorption is strictly a dysfunction of the absorptive process in the small gut resulting from reduction in the size of the absorptive surface caused by responses to factors including inflammation, infection, surgical resection, and infiltration. Various genetic defects also lead to malabsorption of specific substances (e.g., glucose-galactose malabsorption, zinc deficiency in the congenital disorder acrodermatitis enteropathica). In clinical practice, however, the term malabsorption is often used to encompass all aspects of impaired digestion and absorption.

In the following three sections, the digestion and absorption of carbohydrates, fats, and proteins will be discussed separately. It must be remembered, however, that a complex interplay takes place among nutrients, regulatory peptides, enzymes, gallbladder and pancreatic function, the microbiota of the gut, and bowel motility, leading to an integrated absorptive process that commences with the ingestion of food and culminates in the excretion of feces.

Digestion and absorption of carbohydrates

After the action of salivary and pancreatic α-amylases on dietary starch and glycogen, the carbohydrate content of the small intestine consists of newly formed maltose; ingested monosaccharides; dietary disaccharides such as lactose, sucrose, maltose, and trehalose; oligosaccharides such as dextrins and maltotriose; and indigestible oligosaccharides and polysaccharides such as cellulose, agar, and other dietary fibers.

The brush border enzymes with disaccharidase and oligosaccharidase activity are listed in Table 52.1 . The sucrase-isomaltase complex comprises most (80%) of the sucrase, isomaltase, and maltase activity of the small intestine. It hydrolyzes sucrose to its constituent monosaccharides, cleaves glucose from α-limit dextrins with 1, 6 bonds, and hydrolyzes maltose. The activity of the complex is fourfold to fivefold greater in the jejunum than in the ileum. Changes in diet have a marked effect on the expression of the complex; starvation leads to a rapid decline in activity that is rapidly restored on refeeding. Secretion of all small intestinal saccharidases may decrease with infection or inflammation of the small bowel to the extent that carbohydrate malabsorption occurs, leading to diarrhea, flatulence, and weight loss. Paradoxically, diabetes mellitus causes a striking increase in sucrase-isomaltase activity; an increase is also observed in monosaccharide and amino acid transport.

The lactase–phlorizin hydrolase complex is the only brush border enzyme able to hydrolyze lactose and is therefore essential for the survival of mammals early in life. This complex also has glucosylceraminidase, β-glycosidase, and phlorizin hydrolase activities. Infectious and inflammatory diseases greatly reduce lactase–phlorizin hydrolase activity, leading to symptomatic intolerance to milk (bloating, abdominal pain, diarrhea, and flatulence). Recovery of enzyme activity after intestinal disease may be slow. The activity of the complex is resistant to starvation. The developmental regulation of lactase is discussed later in the section on disaccharidase deficiencies. Also present in the brush border is the α-glucosidase maltase-glucoamylase, which removes individual glucose molecules from the nonreducing end of α(1,4) oligosaccharides and disaccharides. This enzyme accounts for approximately 20% of the total maltase activity of the small intestine. Trehalase is also found in the brush border of the small intestine and hydrolyzes trehalose, an α(1,1) disaccharide of glucose found in yeast and mushrooms. The developmental pattern of trehalase appears to follow that of sucrase-isomaltase.

In addition to their actions on disaccharides, the brush border enzymes further hydrolyze the products of amylase action, including maltose, maltotriose, and α-limit dextrins. The brush border enzymes appear to act in an integrated manner in that a flow of substrate occurs from glucoamylase and isomaltase to sucrose, producing the monosaccharides glucose, galactose, and fructose. These monosaccharides are transported into enterocytes by facilitative transport systems such as the sodium-dependent glucose (and galactose) transporter (SGLT1) and the GLUT5 transporter, which transports fructose across the apical membrane of the enterocyte. Subsequently absorbed glucose and fructose are transported across the basolateral membrane, out of the enterocyte, and into the portal system by the GLUT2 transporter.

It is increasingly being recognized that the limiting factor in carbohydrate digestion and absorption may be diffusion from the intestinal lumen to the membrane surface where the enzymes are localized. Normally, little disaccharidase activity is seen in the luminal contents. For most oligosaccharides (with the exception of lactose), hydrolysis is rapid and transport is the rate-limiting step in reducing the concentration of monosaccharides and the osmotic load in the gut. When the transport system is operating at its maximum rate but monosaccharide concentration is still high, inhibition of hydrolases by their monosaccharide products (i.e., product inhibition) slows hydrolytic activity, keeping monosaccharide concentrations relatively constant, thereby controlling osmotic load and water concentration in the gut. The importance of this control is evident from the consequences of intestinal disorders in which ingested disaccharide is not split and absorbed, leading to osmotic fluid retention within the lumen, increased fluid secretion into the gut, and increased intestinal motility. Enteric bacteria ferment the unabsorbed sugars producing hydrogen, carbon dioxide, and organic acids, causing abdominal discomfort such as bloating, abdominal distention, cramping, and looseness of bowel motions. Absorption of fermentation products may lead to metabolic acidosis. In the large bowel, the presence of carbon dioxide and organic acids decreases pH and keeps the osmolality high, so that water reabsorption is decreased. The result is an acidic, liquid stool. Normally, however, accumulation of monosaccharide products does not occur, because the transport system is sufficiently fast to remove them. Mucosal lactase activity is the lowest of all the disaccharidases; for lactose, the rate-limiting step in absorption is thought to be hydrolysis. Lactase activity is not increased by feeding large amounts of lactose, as is the case for maltase and sucrase with maltose and sucrose feeding, respectively. Lactase, maltase, and sucrase all show circadian rhythms in their activities; minimum and maximum rates of secretion may vary by a factor of two.

Carbohydrate digestion is not always complete in the small intestine. It is likely that some starch and sucrose, as much as 10% of that ingested, normally passes undigested and unabsorbed into the colon. It has been estimated that colonic bacteria require 70 g of carbohydrate per day. Much of this is derived from endogenous sources, such as glycoproteins from GI secretions, with the remainder coming from unabsorbed dietary carbohydrate and dietary fiber. Up to 15% of the carbohydrate from white bread reaches the colon, and the effects of indigestible oligosaccharides on reaching the large bowel are well known. Bacterial action creates short-chain fatty acids that are rapidly absorbed by the colonic mucosa and are thought to provide fuel for the colonocytes. Starch and oligosaccharides are osmotically active and draw water into the gut and retain luminal fluidity. The colon, however, can absorb up to four times the normal colonic water load; for this reason, diarrhea is not always present in oligosaccharide malabsorption.

Digestion and absorption of lipids

The recommended daily fat intake in Europe and North America is 70 to 85 g. Less than 5 g/24 h is recoverable in feces, indicating the overall efficiency of the normal processes of fat digestion and absorption. Most dietary fat is in the form of long-chain triacylglycerols (triglycerides). Pancreatic lipase is quantitatively the most important hydrolytic enzyme, but the contribution of gastric lipase to overall hydrolysis should not be underestimated. Gastric lipase is secreted by the gastric mucosa and normally accounts for up to 17.5% of fatty acids released from triglycerides following a meal. The enzyme has a wide pH optimum and is active in both the stomach and duodenum. This nonpancreatic lipase may have a significant role in lipid digestion when pancreatic function is impaired and in the neonatal period before pancreatic lipase activity is fully developed. A lingual lipase is also produced but is thought to be of little significance in humans.

Fats are first emulsified in the stomach by its churning action and are stabilized by interaction with luminal lecithin and protein fragments. The lingual and gastric lipases do not require bile salts or cofactors for their action; they have a pH optimum of 3 to 6, and their action produces 1,2-diacylglycerols and fatty acids. These products further stabilize the surface of the triglyceride emulsion and in the duodenum promote the binding of pancreatic colipase. In addition, the liberated fatty acids stimulate release of cholecystokinin (CCK) from the duodenal mucosa.

Pancreatic lipase, in the presence of bile salts and colipase, acts at the oil-water interface of the triglyceride emulsion to produce fatty acids and 2-monoacylglycerols. Colipase is secreted by the pancreas as an inactive proenzyme, that is then converted to the active form by trypsin. Other significant enzymes involved in the breakdown of fats are cholesterol ester hydrolase, phospholipase A2, and a nonspecific bile salt-activated lipase.

Only a small proportion of ingested triacylglycerol is completely hydrolyzed to glycerol and fatty acids. These products form micelles with bile salts and lysophosphoglycerides; the micelles convey the nonpolar lipid molecules from the lumen to the epithelial cell surface and dissociate there to produce a high concentration of monoglycerols, lysophosphoglycerides, and fatty acids, which partition into the mucosal cell. Absorption involves both passive and active transport processes and is facilitated by a fatty acid–binding protein in the cytosol of the cell that has a high affinity for fatty acids. Within the cell, triacylglycerols are resynthesized from the absorbed 2-monoacylglycerols and fatty acids. The triacylglycerols, together with phospholipids, cholesterol and its ester, fat-soluble vitamins, and apolipoprotein B-48, are formed into chylomicrons that are then released by exocytosis into the lymphatic system of the small bowel. The absorption of long-chain fatty acids is facilitated by a number of transmembrane fatty acid transport proteins.

From the lymphatic system, chylomicrons enter the bloodstream via the thoracic duct and are distributed to the liver, adipose tissue, and other organs. Medium- and short-chain fatty acids (chain length <12 carbon atoms) in mixed triglycerides are preferentially split by lipases and pass into the aqueous phase, from which they are rapidly absorbed. Medium-chain triglycerides can be absorbed without complete lipolysis and in the absence of bile. They do not require micellar solubilization and are transported from the intestinal epithelial cells predominantly via the hepatic portal vein. Fig. 52.3 summarizes the processes involved in fat absorption and conditions that compromise the efficiency of one or more stages in these processes that can result in fat malabsorption.

Digestion and absorption of proteins

The average daily intake of protein in developed countries is approximately 100 g compared with an estimated requirement for adults of 50 to 70 g. Another 50 to 60 g of protein enters the intestinal tract daily in GI secretions and from desquamated mucosal cells. Normal daily fecal loss of protein is about 10 g.

Protein digestion is initiated in the stomach by the action of pepsin in a highly acidic medium. The acidity also helps denature dietary proteins, unfolding the polypeptide chains for better access by the gastric, pancreatic, and intestinal proteolytic enzymes. The polypeptides and amino acids produced in the stomach by the action of pepsin are potent secretagogues for hormones that stimulate the pancreas and intestine. Stimulated pancreatic secretion contains proenzymes of the proteolytic enzymes trypsin, chymotrypsin, elastase, exopeptidases, and carboxypeptidases. Stimulation of the intestine by GI hormones liberates several proteolytic enzymes from the brush border. One of them, enterokinase, selectively cleaves a hexapeptide from the N-terminus of trypsinogen to form trypsin. Trypsin then activates more trypsin (autocatalysis) and also converts other pancreatic proenzymes into their active forms. Proteolytic enzymes may be endopeptidases (e.g., pepsin, trypsin, chymotrypsin, elastase), which hydrolyze peptide bonds within the polypeptide chain, or exopeptidases, which hydrolyze peptide bonds of the terminal amino acids (e.g., carboxypeptidase, aminopeptidase). The action of the pancreatic enzymes on partially digested proteins within the lumen produces peptides that are 2 to 6 amino acid residues in length, as well as single amino acids. The peptides are largely hydrolyzed to single amino acids by the aminopeptidases and dipeptidases of the brush border before absorption, although some dipeptides and tripeptides are absorbed and hydrolyzed to amino acids by cytosolic peptidases within the enterocytes. Multiple carrier systems with overlapping specificities for the 20 essential amino acids are involved in the transport of amino acids into cells. Absorption of amino acids by these transport systems is faster in the jejunum than the ileum. The amino acids pass across the enterocyte basolateral membrane by passive diffusion and by active transport systems, which are distinct from those at the brush border membrane. The underlying rich vascular plexus is drained by the portal circulation and it is by this route that absorbed amino acids reach the liver and then the systemic circulation.

Individuals with achlorhydria or total gastrectomy have normal protein digestion and absorption because small intestinal function compensates for the lack of pepsin activity. Pancreatic and small intestinal diseases are the major causes of protein maldigestion and malabsorption. However, fecal loss of protein rarely becomes significant in pancreatic insufficiency until trypsin secretion falls to less than 10% of normal. Two rare disorders, trypsin deficiency and enterokinase deficiency, have far-reaching effects on the efficiency of protein digestion, as would be expected from their roles in the activation of proteolytic proenzymes.

Mucosal diseases may affect protein assimilation through a number of mechanisms. Reduction in the number of mucosal cells decreases peptidase activity in the intestine and the absorptive capacity for amino acids. Disease may increase the turnover of intestinal cells and their rate of desquamation. This cell loss, together with increased losses of plasma proteins from the damaged intestinal surface, can cause a negative nitrogen balance. Surgical resection of the intestine not only reduces the total absorptive surface area but also may remove a segment of the gut that is specialized for absorption of certain nutrients (e.g., resection of the distal ileum removes the active transport system for vitamin B ₁₂ –intrinsic factor complex). Resection also may alter intestinal motility leading to stasis and bacterial overgrowth that can intensify a negative nitrogen balance. Also, rare hereditary defects in amino acid transporters (e.g., Hartnup disease) may produce distinct syndromes.

Helicobacter pylori

In 1985, an association was made between the presence of a spiral-shaped bacterium, H. pylori, and peptic ulcer diseases. H. pylori is now accepted to be the predominant cause of gastric and duodenal ulcers, the remainder being associated with the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDS) and, rarely, gastrinomas. Most estimates suggest that H. pylori is present in the mucus layer of the stomach in half of the world’s population. In Europe 30 to 50% of adults and in the United States at least 20% of the adult population is infected with the bacterium. Chronic infection produces an inflammatory response (gastritis) and increases the risk for developing a peptic ulcer (3- to 10-fold) and/or adenocarcinoma (2- to 10-fold). Up to 90% of gastric cancer patients are infected with H. pylori compared to 40 to 60% of age-matched controls. ^, In a European study comparing the prevalence of H. pylori versus gastric cancer rates in 13 countries, a significant correlation was found between infection rate and gastric cancer incidence and mortality. H. pylori may cause dyspepsia in the absence of an ulcer, and current recommendations suggest a low threshold for testing for H. pylori and some advocate treatment without testing .

The mode of transmission of H. pylori is unclear. In many cases the infection appears to originate in childhood, presumably by the fecal-oral route, because the prevalence is higher in developing countries and is inversely related to food hygiene. Almost all individuals infected with H. pylori develop chronic gastritis, but only 10% of cases manifest as peptic ulcers. H. pylori infection predominantly affects the gastric mucosa, with the antrum usually the most densely colonized area. At least 95% of patients with duodenal ulcers have H. pylori infection, and eradication of the organism results in healing of the ulcer and a reduction in relapse rates. There is considerable variation in whether an individual infected with H. pylori will develop clinically significant disease. This variation is governed by a number of factors including the site of infection, virulence factors (e.g., vacuolating cytotoxins [VAC], CagA protein), mucus secretion, and extent of pepsinogen secretion. Infection of the mid-body of the stomach is the commonest form, occurs in people with a highly active immune system, and involves a type of H. pylori with low expression of CagA and VAC. However, if the infection is in the antrum, the inflammation causes the G cells to become hyperactive with a resulting disproportionate secretion of gastrin in response to food and gastric distention and consequent increases in acid output. Basal acid output has been shown to be higher in H. pylori –infected subjects, and this resolves after eradication of the organism. Hypergastrinemia is believed to be only one of the mechanisms leading to increased acid output. Studies using the neuropeptide gastrin-releasing peptide (GRP) suggest that interference with control mechanisms inhibiting acid production may be responsible for the increased acid output in H. pylori infection.

H. pylori produces urease, and hydrolysis of this endogenously produced urea to bicarbonate and ammonia may create a more hospitable environment for the survival of the organism in the stomach. This ability of H. pylori to hydrolyze urea forms the basis of urea breath tests and direct urease tests on gastric biopsy samples.

Gastric acid secretion and gastrinomas

Before the discovery of the role of H. pylori, patients with gastric or duodenal ulcers were often tested for hyperacidity of the stomach, either in the basal state or after stimulation. Patients with duodenal ulcers are typically hypersecretors of acid, whereas those with peptic ulcers are more often normal or low secretors, but there was significant overlap between the two groups of patients. Collection of gastric juice and analysis of acid output was at one time extensively carried out in the investigation of possible gastrinomas. This invasive technique has now been replaced by the greater availability of plasma gastrin measurements, endoscopy, and imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and octreotide scanning.

Celiac disease