The gastrointestinal tract

Chapter 6 The gastrointestinal tract


The digestion and absorption of food is a complex process, which depends on the integrated activity of the organs of the alimentary tract. Food is mixed with the various digestive fluids, which contain enzymes and cofactors, and is broken down into small molecules that are absorbed by the intestinal epithelium. Polymeric carbohydrates, such as starch, undergo incomplete conversion to mono- and disaccharides, the latter undergoing further hydrolysis by intestinal brush border disaccharidases (e.g. lactase) to allow absorption of the constituent monosaccharides. Proteins are broken down by proteases (secreted as inactive precursors) and peptidases to oligopeptides and amino acids. The absorption of fat is necessarily more complex because most fats are immiscible with water. Mechanical mixing and the action of bile salts create an emulsion of triglycerides (strictly, triacylglycerols, see Chapter 14), which are a substrate for pancreatic lipase. This enzyme converts triglycerides to free fatty acids and monoglycerides. These are then incorporated with bile salts into mixed micelles and are absorbed from these into intestinal epithelial cells, where they are re-esterified.

All these processes require the intimate mixing of enzymes, cofactors and substrates, and the maintenance of the optimum pH for enzyme activity. Disorders of the stomach, pancreas, liver and small intestine can each result in the malabsorption of nutrients.

In addition to its importance in the absorption of water and nutrients, the mucosal lining of the gastrointestinal tract has an important barrier function, providing protection against the action of hydrogen ions and enzymes, and preventing invasion of its wall by its normal bacterial flora. The small intestine also contributes to this protective function through its immune function. In gastrointestinal disease, this barrier function may be compromised, and bacteria may gain access to the circulation and cause septicaemia.

The gut also secretes numerous hormones: many of these act on the gut itself or its related organs; others are involved in signalling hunger and satiety to the brain, and thus in appetite control.

The stomach

In the stomach, food mixes with acidic gastric juice, which contains the proenzyme of pepsin (pepsinogen), and intrinsic factor, essential for the absorption of vitamin B12. Secretion of gastric juice is under the combined control of the vagus nerve and the hormone gastrin.

Gastrin is secreted by G-cells in the antrum of the stomach itself and has several physiological functions (Fig. 6.1). It is a polypeptide hormone, present in the bloodstream in various forms (e.g. G-14, G-17 and G-34, containing 14, 17 and 34 amino acids, respectively). Other gastrin molecules have also been identified in the blood. The physiological significance of this heterogeneity is not known, but G-17 and G-34 appear to be most important in gastric acid secretion. All the variants have an identical C-terminal amino acid sequence.

Gastric disorders and investigation of gastric function

Biochemical investigations are of limited use in the diagnosis of gastric disorders: the stomach can be directly inspected by endoscopy, and contrast radiography can also provide valuable information. Biochemical tests can be used to investigate conditions in which it is suspected that gastric acid secretion may be abnormal, particularly in atypical or recurrent peptic ulceration.

Most peptic ulceration is associated either with non-steroidal inflammatory drug (NSAID) use, or with colonization of the stomach with Helicobacter pylori. This organism is able to survive in an acid environment and, although it provokes an immunological response in the host, it also has mechanisms for evading host immunity. Once infection has occurred, therefore, it tends to persist unless specifically treated. The effects of infection depend on host, bacterial and environmental factors. Three main patterns are manifest:

The infection can be eradicated with appropriate combinations of antibiotics and an inhibitor of H+,K+-ATPase (i.e. a proton pump inhibitor).

Diagnosis is by serology or stool antigen test. Serum antibodies remain positive for some time after eradication therapy, so their measurement cannot be used for confirming eradication, but the stool antigen test can be used for diagnosis or monitoring. H. pylori can split urea to form ammonia and carbon dioxide, and this is the basis for a breath test, formerly used for diagnosis but now occasionally to confirm eradication or to indicate persisting infection after treatment. The sensitivity of this test is 96% and specificity virtually 100%. Isotopically labelled (13C or 14C) urea is given orally and the isotope is measured in the expired breath. Excretion is increased if infection is present.

Atypical peptic ulceration

In a small number of patients, peptic ulceration is atypical: for example, duodenal ulcers are resistant to medical treatment or recur, or there are multiple or jejunal ulcers. Atypical peptic ulceration is a feature of Zollinger–Ellison syndrome, a rare condition in which hypergastrinaemia is caused by a gastrinoma of the pancreas, duodenum or, less frequently, the G-cells of the stomach. Approximately 60% of gastrinomas are malignant, and in approximately 25% of cases they occur as part of a syndrome of multiple endocrine neoplasia (MEN) (see Chapter 18). Plasma gastrin concentrations typically exceed 200 ng/L (normal <50 ng/L). In addition to having recurrent or atypical peptic ulceration, patients sometimes have steatorrhoea, owing to inhibition of pancreatic lipase by the excessive gastric acid.

The first-line biochemical test in such patients is the measurement of fasting plasma gastrin concentration. This is frequently elevated in patients with gastrinomas, but some have normal or only slightly elevated concentrations. There are other causes of hypergastrinaemia (Fig. 6.2), including achlorhydria, which most frequently occurs in patients with atrophic gastritis but is also present in pernicious anaemia; it can occur in association with gastric carcinoma, and may be present even in patients with peptic ulceration. If the cause of hypergastrinaemia is in doubt and in patients with atypical peptic ulceration but whose gastrin concentrations are not clearly elevated, it may be helpful to measure plasma gastrin concentration following the administration of secretin. This hormone increases gastrin secretion from gastrinomas, but reduces it or has no effect in hypergastrinaemia from other causes. Unfortunately, supplies of secretin for clinical use may be difficult to obtain. Measurement of gastric acid secretion may also help to distinguish between the causes of hypergastrinaemia. It is typically >15 mmol/h in patients with gastrinomas but low and resistant to stimulation in patients with achlorhydria. Maximal gastric acid secretion can be measured by the pentagastrin test. Protocols for the test vary, but, in essence, it involves measurement of acid in fluid aspirated through a nasogastric tube in the resting state and after the administration of pentagastrin, a synthetic analogue of gastrin. Basal acid secretion is normally <10 mmol/h in males (<6 mmol/h in females); stimulated secretion is normally <45 mmol/h in males and <35 mmol/h in females.

Zollinger–Ellison syndrome is treated by surgical removal of the tumour, where possible. Chemotherapy and long-term treatment with inhibitors of gastric acid secretion may also be necessary and may be the only possible treatment if the tumour cannot be resected.

It should be noted that inhibitors of gastric acid secretion can themselves cause increased gastrin secretion: H2-inhibitors should be stopped three days, and proton pump inhibitors two weeks, before taking blood for gastrin measurement. As the hormone is very labile, the blood specimen used to be mixed with aprotinin, a protease inhibitor, immediately after venesection, to prevent degradation. However, aprotinin has been withdrawn from clinical use and so, if it is unobtainable, samples must just be separated and frozen as quickly as possible.

The pancreas

The pancreas is an essential endocrine organ producing insulin, glucagon, pancreatic polypeptide and other hormones; its endocrine functions are discussed in Chapter 11. The exocrine secretion of the pancreas is an alkaline, bicarbonate-rich juice containing various enzymes essential for normal digestion: the proenzyme forms of the proteases, trypsin, chymotrypsin and carboxypeptidase, and the lipolytic enzyme lipase, colipase and amylase.

The secretion of pancreatic juice is primarily under the control of two hormones secreted by the small intestine: secretin, a 27 amino acid polypeptide, which stimulates the secretion of an alkaline fluid, and cholecystokinin (CCK), which stimulates the secretion of pancreatic enzymes and contraction of the gallbladder. Like gastrin, CCK is a heterogeneous hormone, comprising between 83 and 5 amino acids. Some forms are present in parts of the central nervous system and appear to function as neurotransmitters. Both secretin and CCK are secreted in response to the presence of acid, amino acids and partly digested proteins in the duodenum.

Pancreatic disorders and their investigation

The major disorders of the exocrine pancreas are acute pancreatitis, chronic pancreatitis, pancreatic cancer and cystic fibrosis. Biochemical investigations are essential in the diagnosis and management of the first of these, of limited use in the second, and of little use in the third. Cystic fibrosis, an inherited metabolic disease causing progressive loss of pancreatic function, is discussed in Chapter 16. Clinical evidence of impaired exocrine function is usually only seen in advanced pancreatic disease. Endocrine function is usually well preserved, although glucose intolerance or frank diabetes can develop in severe or advanced disease. Endocrine disease of the pancreas is discussed in Chapter 11.

Acute pancreatitis

This condition presents as an acute abdomen, with severe pain and a variable degree of shock. The most frequent known causes are excessive alcohol ingestion, gallstones and as a complication of endoscopic retrograde pancreatography (ERCP); many cases are idiopathic. Less common causes include infection (usually viral), hypertriglyceridaemia and hypercalcaemia. The pancreas becomes acutely inflamed and, in severe cases, haemorrhagic.

image Case history 6.1

A 53-year-old man, who admitted to a heavy alcohol intake over many years, developed severe abdominal pain, which radiated through to the back. The pain had started quite suddenly, 18 h before admission to hospital. He had no previous history of gastrointestinal disease. On examination, the patient was mildly shocked, and his abdomen was tender in the epigastric region, with slight guarding. There was no evidence of either intestinal obstruction or perforation of a viscus on radiographic examination. Blood was taken for urgent biochemical investigation.

The initial lesion involves intracellular activation of enzyme precursors, leading to the generation of oxygen free radicals and an acute inflammatory response. This may extend beyond the pancreas as systemic inflammatory response syndrome (SIRS) and lead to adult respiratory distress syndrome (ARDS), and circulatory and renal failure. Sepsis, probably as a result of bacterial translocation from the gut, is a life-threatening complication. Some degree of organ failure occurs in approximately 25% of patients, and the mortality is 5–10%.

The clinical diagnosis is supported by finding a high serum amylase activity. This enzyme is secreted by salivary glands and the exocrine pancreas. Its activity in serum is usually (although not invariably) raised in acute pancreatitis, levels >10 times the upper limit of normal (ULN) being virtually diagnostic. However, the increase may not be so great, and elevated levels may be seen in other conditions presenting with acute abdominal pain, particularly perforated duodenal ulcer (Fig. 6.3). Amylase is a relatively small molecule, and is rapidly excreted by the kidneys (hence the increase in activity in renal failure); in mild pancreatitis, rapid clearance may be reflected by a normal serum level but increased urinary amylase. Extra-abdominal causes of a raised plasma amylase activity rarely cause increases of >5 times the ULN. Macroamylasaemia is an example of a high plasma enzyme activity being due to reduced clearance. In this condition, amylase becomes complexed with another protein (in some cases, an immunoglobulin) to form an entity of much greater apparent molecular weight; renal clearance is reduced as a result. This has no direct clinical sequelae but can misleadingly suggest the presence of pancreatic damage.

Measurement of the pancreas-specific isoenzyme of amylase can improve the diagnostic specificity of plasma amylase determinations. Measurement of serum lipase activity has been reported to be a more specific test for acute pancreatitis, but the test is little used in the UK. A combination of lipase and amylase measurement has been reported to have specificity and sensitivity of approximately 90%.

In severe pancreatitis, methaemalbumin may be detectable in the plasma, but this finding is not sufficiently consistent to be of diagnostic value. The plasma of patients with pancreatitis may be lipaemic (due to hypertriglyceridaemia), and there may be a mild increase in bilirubin concentration and alkaline phosphatase activity.

Several prognostic scoring systems that include biochemical data have been developed for acute pancreatitis to identify patients at greatest risk who should be managed in an intensive care facility. Three or more Ranson’s criteria (Fig. 6.4) constitute severe pancreatitis: mortality is <1% if only one or two signs are present, but >40% with five or more. The APACHE-II scoring system (applicable to many acute conditions) is more complicated but more powerful: it is based on the measurement of 12 physiological measurements, the patient’s age and evidence of chronic illness on admission. A plasma C-reactive protein concentration of >150 mg/L is also a good marker of disease severity.

Apr 3, 2019 | Posted by in BIOCHEMISTRY | Comments Off on The gastrointestinal tract
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