The alimentary system

Carbohydrate digestion

The predominant carbohydrates in the diet are

• Starch and glycogen (polysaccharides)

• Sucrose and lactose (disaccharides)

• Fructose (monosaccharide).

Starch and glycogen are polymers comprising chains of glucose molecules joined together by α-1,4 glycosidic bonds and, at branch points, by α-1,6 glycosidic bonds. Salivary and pancreatic amylases catalyse the hydrolysis of the interior α-1,4 bonds but do not split either the terminal α-1,4 glycosidic bonds or the α-1,6 glycosidic bonds at the branches of starch and glycogen. The products of amylase action are maltose (a disaccharide), maltotriose (a trisaccharide) and α-limit dextrins (branched oligosaccharides) ( Fig. 15.3 ) . However, there are no transport systems for the absorption of these carbohydrates in the intestine. The oligosaccharides derived from starch, together with maltose, sucrose and lactose, are further digested by enzymes present on the brush border of enterocytes to their monosaccharides – glucose, galactose and fructose ( Table 15.2 and Clinical box 15.2 ).

Table 15.2

Action of disaccharidases in the brush border of enterocytes

Enzyme	Substrate	Products
Glucoamylase (maltase)	Maltose Maltotriose	Glucose Glucose
	α-Limit dextrins	Glucose
Isomaltase (α-dextrinase)	α-Limit dextrins	Glucose
Sucrase	Sucrose	Glucose and fructose
	Maltose	Glucose
	Maltotriose	Glucose
Lactase	Lactose	Glucose and galactose

Clinical box 15.2

Enzyme deficiency

Deficiencies in enzymes concerned with carbohydrate digestion prevent the breakdown of oligo- and di-saccharides to monosaccharides that can be absorbed; therefore, these are excreted undigested instead. This gives rise to diarrhoea after ingesting foods rich in these particular carbohydrates. A common example is milk intolerance due to lactase deficiency, a condition more common in some Asian and Mediterranean countries. It is not a major clinical problem, as most people with lactase deficiency simply avoid milk. A lactose tolerance test is available, but rarely used for adults.

Protein digestion

The various sources of protein for digestion are from food and also desquamated gastrointestinal cells and digestive secretions. Proteins and polypeptides consist of amino acids linked together by a peptide bond formed between the amino terminal of one amino acid and the carboxy terminal of another (see Ch. 2 ). Protein digestion is accomplished by enzymes (protease or peptidase) hydrolysing peptide bonds either within a polypeptide chain or protein (endopeptidase) or at the free ends (exopeptidase). Thus, a protein may be broken down to a mixture of small polypeptides and amino acids.

Protein digestion in the stomach

Peptic cells in the stomach secrete pepsinogens, the precursor of a family of enzymes known as pepsins. The acid contents of the stomach activate pepsinogens to pepsins and denature the structure of proteins. Pepsin is an endopeptidase and specifically hydrolyses peptide bonds, containing an aromatic L-amino acid such as phenylalanine or tyrosine. Pepsin is inactivated by the alkaline pH found in the duodenum ( Clinical box 15.3 ).

Clinical box 15.3

Enzyme defects in protein digestion

Deficiency in pancreatic enzyme secretion, notably of trypsinogen and chymotrypsinogen, prevents the conversion of dietary protein into polypeptides for absorption. This can occur in chronic pancreatitis, mainly related to sustained alcohol overuse. Cystic fibrosis sufferers have the same enzyme deficiency. The inability of children with cystic fibrosis to digest protein and fat because of the lack of pancreatic enzymes, trypsin and lipase, leads to nutritional deficiencies in essential amino acids, fatty acids and fat-soluble vitamins. High-dose pancreatic enzyme supplements to treat the resulting steatorrhoea, as well as nutritional supplementation, will be necessary.

Protein digestion in the small intestine

Protein digestion in the small intestine occurs owing to the presence of pancreatic proteases ( Table 15.3 ). The most important are trypsin, chymotrypsin and carboxypeptidase. These are secreted as precursors into the duodenum and activated by enteropeptidase (enterokinase) secreted by the duodenal and jejunal mucosa. Enteropeptidase activates trypsinogen to trypsin. Once some trypsin is formed, it acts autocatalytically to convert more trypsinogen to trypsin and also activates chymotrypsinogen to chymotrypsin. Trypsin, chymotrypsin and elastase are endopeptidases and convert protein into polypeptides. Carboxypeptidases release single amino acids from the carboxyl end of polypeptides. The pancreatic proteases active in the lumen of the intestine produce small peptides and some amino acids before being inactivated by autodigestion. The next stage of protein digestion occurs at the brush border of the enterocytes by the action of peptidases present in the luminal membranes to produce small peptides (di-, tri- and tetrapeptides) and single amino acids. Finally, small peptides (usually di- and tri-) are hydrolysed to single amino acids after they have been absorbed into the enterocyte (see Fig. 15.3 ).

Table 15.3

Gastric and pancreatic proteases

Precursor	Activator	Protease
Pepsinogens	Acid	Pepsins
Trypsinogen	Enteropeptidase	Trypsin
Chymotrypsinogen	Trypsin	Chymotrypsin
Procarboxypeptidase	Trypsin	Carboxypeptidase
Proelastase	Trypsin	Elastase

Fat digestion

The majority of the fats in the diet are triacylglycerols (triglycerides), consisting of glycerol to which three fatty acids are attached (see Ch. 2 ). Fats separate from the water phase of the partly digested food in the stomach and empty slowly. The contractile action of the stomach breaks the fat into small droplets and mixes them with the water phase. The nature of fats and their insolubility in the water create difficulties for their digestion by water-soluble lipases. There are three lipases:

• Lingual

• Gastric

• Pancreatic.

The lingual and gastric lipases have acidic pH optima and function in the stomach, producing fatty acids and diacylglycerols (diglycerides) by attacking the outer ester linkages between glycerol and the fatty acids.

The major site of fat digestion is in the small intestine ( Information box 15.1 ). Fat enters the duodenum relatively slowly so that there is time for the process of emulsification and fat hydrolysis. Fat is emulsified into droplets approximately 500–1000 nm in diameter by the action of bile salts, with their hydrophobic side (fat soluble) dissolving in the fat and their hydrophilic side (water soluble) facing outwards in the water of the intestinal fluid. This process is aided by lecithin and cholesterol, which are also found in bile. The emulsifying agents reduce the surface tension of the fat droplets and keep them apart. These actions increase the surface area of the ingested fat. An additional pancreatic enzyme, colipase, anchors pancreatic lipase to the fat/water interface and activates it. This allows an interaction between the water-soluble pancreatic lipase and the ingested fat. Pancreatic lipase (optimum pH 8.0) preferentially hydrolyses the bonds between glycerol and the fatty acid residues at positions 1 and 3 to produce 2-monoacylglycerols (monoglycerides) and free fatty acids. A small quantity of the 2-monoacylglycerols is hydrolysed to glycerol and a free fatty acid. The presence of fat digestion products, bile salts, cholesterol and phospholipids causes the emulsion to break up into smaller particles, known as mixed micelles, with diameters of up to 5 nm. The bile salts form an outer coat, with the fatty digestion products in the centre. The micelles are small enough to diffuse between the microvilli of the enterocytes.

Information box 15.1

Defects in chemical fat digestion

Failure of secretion of pancreatic lipase and deficiency in bile salts affect fat digestion in the small intestine. Pancreatic lipase deficiency occurs in many conditions, including chronic pancreatitis, carcinoma of the pancreas and cystic fibrosis. Deficiency in bile salts is usually due to obstruction, which may be intra-hepatic, as in cirrhosis of the liver, or extra-hepatic due to gall bladder disease, stones in the biliary tree or tumours. The resulting failure to digest fat leads to the excretion of undigested fat globules in the form of pale, bulky, offensive and sometimes frothy stools that float (steatorrhoea). Steatorrhoea may be confirmed by measuring the fat content of stools. The absorption of fat-soluble vitamins may also be impaired (see later).

General principles of absorption

Most carbohydrate, protein and lipid absorption occurs in the small intestine, the duodenum, the jejunum and the early sections of the ileum. These sites, together with the stomach, are also where orally administered drugs are absorbed. Disease of the membranes through which absorption takes place, and defects in the normal mechanisms for absorption, leads to nutritional deficiencies and also adverse or toxic drug effects. Absorption of solutes may occur by either passive or active processes ( Clinical box 15.4 ).

Clinical box 15.4

Diarrhoea

Disease of the gastrointestinal tract prevents efficient absorption by compromising the transfer of nutrients across the intestinal epithelium. This can be caused by inflammatory processes through infection (gastroenteritis, dysentery and parasitic infestations), immune responses (Crohn disease, ulcerative colitis, coeliac disease, etc.), antibiotic use, hereditary digestive enzyme deficiency, the presence of defective Na ⁺ /glucose transporter (SGLT1) or a reduction in surface area after surgical resection.

Clinically, diarrhoea occurs when there is an increase in daily stool weight to more than 300 g, increased fluid content and stool volume, and there is usually an associated increase in frequency of bowel action. Steatorrhoea occurs when there is impaired fat absorption and the stools have a high fat content. Diarrhoea may be

• Osmotic – when the presence of undigested hypertonic substances draws fluid into the large bowel by osmosis

• Secretory – usually after intestinal resection, in the presence of toxins or laxative use, when fluid and electrolyte absorption is decreased at the same time as an increase in secretion occurs

• Inflammatory – due to damage of the intestinal mucosa through infection or inflammation.

There is increased fluid and electrolyte loss as well as reduced absorption. The fluid and electrolyte loss can lead to severe dehydration and metabolic imbalance. Diarrhoea is one of the leading causes of death among children in developing countries.

There are two types of passive diffusion. These are simple diffusion, where small molecules, such as O ₂ and CO ₂ , and fat-soluble molecules diffuse through the lipid bilayer of the cell membrane, and facilitated diffusion, where the transported molecule moves through the membrane by means of a protein carrier. In a passive process, the absorbed solute will move from a high to a low concentration. Passive processes do not require the use of energy from cellular metabolism.

Water and some solutes pass through membranes at a faster rate than would be expected from a knowledge of the lipid solubility. This suggests that there are routes through the membrane for water and small hydrophilic solutes. These may be in the spaces between the membrane phospholipids and through specific membrane proteins called aquaporins. Ions can diffuse through specific protein ion channels that span the membrane.

In contrast, an active process involves cellular energy to drive an absorbed solute against either a concentration gradient or an electrical gradient, i.e. an ‘uphill’ movement from a low to a high concentration or for a charged solute moving to a region of the same charge, e.g. Na ⁺ ions being transported out of cells. The two types of active transport use adenosine triphosphate (ATP) either directly, as in the Na ⁺ /K ⁺ -ATPase pump, or indirectly as a source of energy to power secondary active transport.

For the absorption of many solutes in the alimentary canal, there are carrier-mediated mechanisms that use the concentration gradient built up as a result of the primary active transport of Na ⁺ . This process is known as secondary active transport. The carriers have binding sites for the organic molecules and for Na ⁺ . The movement of Na ⁺ down its concentration gradient can lead to the simultaneous transfer of the organic molecule into the cell against its concentration gradient. Metabolic inhibitors that block the primary active transport system will lead to inhibition of the secondary active transport system once the potential energy stored in the Na ⁺ concentration gradient across the cell membrane has run down.

Carbohydrate absorption

The carbohydrate digestion products are glucose, galactose and fructose. A small quantity of these sugars is absorbed by passive diffusion through aqueous channels between enterocytes and in the cell membranes. The main transport mechanisms involve carrier proteins in the brush and basolateral borders of enterocytes. All the sugars enter the hepatic portal vein for delivery to the liver.

Protein absorption

The proteases in the gastrointestinal tract produce a variety of peptides and free amino acids for absorption. The enterocytes have a relatively high cytosolic concentration of free amino acids for protein synthesis that, in turn, can make amino acid absorption more difficult. This difficulty is overcome by the absorption of di- and tripeptides that are subsequently hydrolysed by peptidases to release free amino acids within the cell. This hydrolysis maintains a concentration gradient for peptides across the luminal cell membrane. After passing across the basolateral membrane, the absorbed amino acids enter the hepatic portal vein for delivery to the liver.

Amino acid absorption

There are a number of transport systems ( Table 15.4 ) for L-amino acids in the brush border of enterocytes that require the co-transport of Na ⁺ to allow the transfer of amino acids against a concentration gradient by means of secondary active transport. Facilitated diffusion of some amino acids also occurs. The presence of carrier systems working in parallel for single amino acids and small peptides in the intestine enhances the overall absorption of amino acids by allowing the uptake of the same amino acid, e.g. glycine in peptide form, as well as of free amino acid. Five carrier mechanisms are present in the basolateral borders of enterocytes. Three amino acid carriers not requiring Na ⁺ to function transport the intracellular amino acids to the extracellular fluid for diffusion into the blood. The Na ⁺ -requiring carriers provide amino acids from the circulation for protein synthesis in crypt cells.

Table 15.4

Amino acid transport systems in enterocytes

Site and system	Amino acid transporter	Co-transported ion
Apical membrane
B	Neutral amino acids, e.g. alanine	Na +
B o	Neutral and cationic (basic) amino acids, e.g. lysine and also cystine	Na +
b ot	Neutral and cationic amino acids	None
	Anionic (acidic) amino acids, e.g. glutamate, aspartate	2 Na + , 1 H + , inward; 1 K + , outward
y +	Cationic (basic) amino acids, e.g. arginine, lysine	None, but will also co-transport small neutral amino acids with Na +
Imino	Proline and hydroxyproline	Na + and Cl −
β	β amino acids: β-alanine and taurine	Na + and Cl −
Basolateral membrane
A	Most neutral and imino acids	Na +
ASC	Neutral amino acids with 3–4 carbons	Na +
b ot	Neutral and cationic amino acids	None
L	Neutral amino acids with hydrophobic side chain	None
y +	Cationic (basic) amino acids, e.g. arginine, lysine	None but will also co-transport small neutral amino acids with Na +

Fat absorption

The process of fat absorption (see Fig. 15.4 ) differs from that of carbohydrate and proteins. Short- and medium-chain fatty acids (C8–14) and glycerol are water soluble and diffuse directly through the luminal and basolateral membranes of the enterocyte to enter the capillaries. The micelles, containing 2-monoacylglycerols and larger free fatty acids (chain length greater than 14 carbon atoms) in their cores, being water soluble, diffuse through the unstirred layer of water at the surface of the enterocyte at a faster rate than can be achieved by fat digestion products alone. The hydrophobic 2-monoglycerides and free fatty acids are delivered by this mechanism to the enterocytes of the jejunum, where they are absorbed by diffusion through the lipid portions of the surface of the cell membrane.

The absorbed long-chain fatty acids and 2-monoglycerides bind to a fatty acid-binding protein within the enterocyte, thus maintaining the concentration gradient across the cell membrane for these products. The fatty acid-binding protein transfers the fatty acids and 2-monoglycerides to the smooth endoplasmic reticulum for the resynthesis of triglyceride by acyl-CoA synthetase and acyltransferase. The triglyceride is coated with lipoprotein, derived from cholesterol, phospholipid and apoprotein B in the rough endoplasmic reticulum, to form a chylomicron that is transferred to the Golgi apparatus where the protein coat is glycosylated prior to exocytosis across the basolateral membrane. Chylomicrons (diameter 75–600 nm) are too large to enter the capillaries, but can diffuse through spaces in the walls of lacteals (lymphatic vessels) in the villi. The lacteals drain into larger lymphatic vessels, leading to the thoracic lymphatic duct, which, in turn, distributes the lymph to the venous system at the junction of the left subclavian vein and left jugular vein. In contrast to other nutrients, the absorbed lipids are available for either energy production or storage in all organs of the body before reaching the liver.

Bile salt absorption

The bile salts are ionised at intestinal pH and require a carrier mechanism for their absorption. The sodium-dependent carrier is present in the enterocytes of the terminal ileum. Absorption is by means of secondary active transport similar to that described for glucose or amino acid transport. The absorbed bile salts enter the venous system draining the ileum and are transported to the liver in the enterohepatic circulation. The liver extracts the bile salts and secretes them into the bile. The bile salt pool may recirculate two or three times during a large meal.

Vitamins

Vitamins (A, B, C, D, E and K) are organic compounds that the body is unable to synthesise; therefore, they must be absorbed from the small intestine (see Ch. 16 ).

Vitamin B ₁₂

The absorption of vitamin B ₁₂ (cobalamin) involves a complex series of events. Vitamin B ₁₂ in food is bound to proteins. The action of acid and pepsins in the stomach releases the vitamin B ₁₂ . The free vitamin B ₁₂ binds to glycoproteins, known as R proteins, that are present in the stomach contents derived from saliva and gastric juice. Another glycoprotein capable of binding vitamin B ₁₂ is intrinsic factor secreted by parietal cells. The affinity of intrinsic factor for ingested B ₁₂ is less than that of R proteins; therefore, most of the vitamin B ₁₂ in the chyme leaving the stomach and entering the intestine is bound to R protein. Once in the intestine, the pancreatic proteases digest the R protein and vitamin B ₁₂ is free once again. It binds to intrinsic factor, which is resistant to digestion by pancreatic proteases. The vitamin B ₁₂ –intrinsic factor complex passes along the small intestine to the terminal ileum where there are receptors in the brush borders of the enterocytes for the vitamin B ₁₂ –intrinsic factor complex. Binding of the vitamin B ₁₂ –intrinsic factor complex to the membrane receptor triggers endocytosis (receptor-mediated endocytosis) of the complex into the cell. Vitamin B ₁₂ is released from the complex within the cell and exported across the basolateral border and diffuses into the blood where it binds to transcobalamin II, a transport protein ( Information box 15.2 ).

Information box 15.2

Vitamin B ₁₂ malabsorption

Vitamin B ₁₂ deficiency is caused by the malabsorption of vitamin B ₁₂ . The commonest cause is pernicious anaemia . There is atrophic gastritis leading to a failure in the production of intrinsic factor . This is an autoimmune condition and is associated with other autoimmune diseases, such as thyroid disease and vitiligo. It is sometimes also associated with gastric carcinoma. Intrinsic factor antibodies are present, inhibiting the binding of intrinsic factor to B ₁₂ in the stomach and also blocking the vitamin B ₁₂ –intrinsic factor complex coupling to receptors in the terminal ileum, where B ₁₂ would normally be absorbed. A 3–6-year store of vitamin B ₁₂ is present in the liver, and, therefore, patients with pernicious anaemia may take years to develop symptoms of anaemia. Treatment is by intramuscular injections of vitamin B ₁₂ . Other causes of vitamin B ₁₂ malabsorption include coeliac disease, surgical resection of the stomach or ileum, and the long-term use of drugs such as proton pump inhibitors.

Fat-soluble vitamins

The fat-soluble vitamins A, D, E and K entering the small intestine are solubilised by diffusion into micelles containing bile salts and fat digestion products (see Ch. 16 ). Absorption of these vitamins occurs by diffusion across the brush border of the enterocyte together with fatty acids and monoglycerides. The fat-soluble vitamins are exported to the lymphatic system in chylomicrons ( Information box 15.3 ).

Information box 15.3

Vitamin D deficiency

Chronic steatorrhoea could lead to malabsorption of fat-soluble vitamins. Although this could be the cause of vitamin D deficiency ( rickets , osteomalacia ), other factors are anticonvulsant therapy and renal failure, which interfere with vitamin D metabolism.

Absorption of electrolytes and water

Each day, approximately 9 L of fluid enters the alimentary canal. This is derived from the diet (2 L) and the digestive secretions (7 L) ( Fig. 15.5 ) . In health, approximately 99% of the water and electrolytes are absorbed into the blood as the fluid passes along the small and large intestine. The major site of fluid absorption is the jejunum and ileum (8.5 L), with a relatively small quantity being absorbed from the colon (0.4 L). The faeces contain approximately 0.1 L of water. The absorption of water is secondary to the uptake of electrolytes, in particular Na ⁺ and Cl ⁻ , sugars and amino acids.

Pathways for electrolyte and water absorption

The electrolytes and water may be absorbed by passing between the enterocytes (paracellular route) via aqueous channels, through the tight junctions linking the cells together. The alternative route is by passing through the cells (transcellular route). This may involve both carrier-mediated mechanisms and passage through water-permeable channels ( Table 15.5 ).

Table 15.5

Electrolyte transport in the small and large intestine

Intestinal region	Na +	K +	Cl −
Duodenum and jejunum	Actively absorbed Co-transport with glucose, galactose, amino acids Co-transport with Cl − Counter transport exchange for H + Diffusion through aqueous channels	Passively absorbed by diffusion through paracellular pathways as the luminal concentration rises after water absorption	Passively absorbed Co-transport with Na + Counter transport exchange for Diffusion through paracellular channels	Absorbed as CO 2 following neutralisation of secreted H +
Ileum	Actively absorbed as above but reduced importance of co-transport with organic solutes	Passively absorbed as above	Passively absorbed Counter transport exchange for Diffusion through paracellular channels	Passively absorbed Counter transport in exchange for Cl − Diffusion
Colon	Actively absorbed Via Na + channels Co-transport with Cl − Counter transport exchange for H +	Secretion Passive leakage from enterocytes through K + channels in their apical membranes when luminal concentration is <25 mmol/L Actively reabsorbed by luminal H + /K + ATPase during K + deprivation or depletion	Passively absorbed Co-transport with Na + Counter transport with Diffusion through paracellular channels Co-transport with short-chain fatty acids	Secretion Counter transport exchange with Cl −
	Stimulated by aldosterone	Stimulated by aldosterone

Water movement from the lumen of the intestine may occur via membrane proteins, including the SGLT1, sodium/glucose co-transporter and channels named aquaporins that allow the passage of water. The unstimulated SGLT1 acts as a water-permeable protein channel. When stimulated by the presence of Na ⁺ and glucose in the intestinal lumen, it co-transports water together with Na ⁺ and glucose into the intestinal mucosal cell. In addition, the absorption of water is secondary to organic and ionic solute movement. The transfer of solutes across the intestinal epithelium creates an osmotic gradient between the lumen and the interstitial fluid and blood. Water is absorbed by osmosis via paracellular and transcellular routes (see Fig. 15.3 ). The principle of oral rehydration therapy, used to treat diarrhoea, is based on promoting water absorption, either by means of co-transport or by osmosis, following an isotonic drink containing glucose and electrolytes, including sodium chloride.

Calcium absorption

Dietary calcium is found in a variety of foods including dairy products. Calcium may exist bound to oxalates, phosphates and phytates or in the ionised form (Ca ²⁺ ) in the intestine. Ionised calcium is available for absorption by enterocytes in the upper small intestine. The free Ca ²⁺ concentration in the cell is low, giving rise to a steep concentration gradient between the lumen and the cytoplasm. Ca ²⁺ ions bind to a protein in the brush border and are transported down their concentration gradient into the cell. The free Ca ²⁺ concentration in the cytoplasm is kept low by Ca ²⁺ binding to calcium-binding proteins that are sequestered in intracellular organelles such as the endoplasmic reticulum. Ca ²⁺ ions are exported across the basolateral border of the cell against an electrochemical gradient by active transport. There are two mechanisms:

• Ca ²⁺ -ATPase, which uses energy derived from the hydrolysis of ATP to transfer Ca ²⁺ out of the cell

• Na ⁺ /Ca ²⁺ exchanger, in which Na ⁺ moving down its electrochemical gradient into the cell drives Ca ²⁺ extrusion.

The Ca ²⁺ -ATPase mechanism is the more important one.

Calcium absorption is regulated by 1,25-dihydroxycholecalciferol, the active form of vitamin D, which stimulates the synthesis of both calcium-binding proteins and Ca ²⁺ -ATPase (see Ch. 10 ). Note: a high dietary phytate content, as in chapatti flour, may inhibit calcium absorption.

Iron absorption

Dietary iron is present in two forms:

• The haem portion of haemoglobin, myoglobin and cytochromes

• An insoluble, non-absorbable state complexed with phytate, tannins and plant fibres. Insoluble iron salts may also form with hydroxide, phosphate and bicarbonate found in digestive secretions.

The acidic conditions of the stomach mobilise the iron compounds by converting the ions from the ferric (Fe ³⁺ ) to the ferrous (Fe ²⁺ ) state. Similarly, vitamin C reduces iron to the ferrous state and also forms soluble complexes with it that enhance absorption. Ferric ions are reduced to ferrous ions by duodenal cytochrome b ferric reductase in the brush border of the duodenal enterocyte.

The enterocytes of the duodenum absorb haem and ferrous ions by two separate mechanisms:

• 1

  Haem is absorbed by endocytosis and digested in the enterocyte by haem oxidase to release ferric ions, carbon monoxide and biliverdin. The ferric ions are reduced to ferrous ions that bind to ferroportin 1 in the basolateral membrane for export from the cell.

• 2

  Ferrous ions and a proton bind to a divalent metal transporter to cross the brush border. The movement of a proton down its concentration gradient into the enterocyte is the driving force for ferrous ion absorption. In the cytosol, ferrous ions either bind to a storage protein, apoferritin, to form ferritin or are transferred to ferroportin 1 in the basolateral borders of the cell for export to the tissue fluid.

An additional protein, hephaestin, is considered to have a role in the export of iron from the enterocytes to the plasma. It may be involved in the release of iron from its storage sites and transfer to ferroportin 1 for export to the tissue fluid. Ferrous ions diffuse into the blood and are transported around the body in association with transferrin, a plasma protein.

The absorption of iron needs to be regulated because

• There are no active excretory mechanisms

• This metal plays an essential biological role in oxygen transport and redox reactions in cellular respiration.

In addition, iron is involved in the formation of reactive oxygen species that may be useful in killing bacteria. However, reactive oxygen species are also toxic to cells when large quantities are produced following excessive iron accumulation (see Ch. 16 and Information box 15.4 ).

Information box 15.4

Absorption of oral iron

The ferrous state is more readily absorbed than ferric iron, and oral iron supplement formulations are usually in the ferrous state. Iron absorption increases during pregnancy and iron-deficiency anaemia. High dietary content of phosphates and phytate (in chapatti flour) can inhibit iron absorption by forming insoluble complexes.

Epigastric region

Typically, pain and tenderness in the epigastrium are referred from the upper abdominal organs, such as the stomach and duodenum. Palpable masses usually arise from the stomach, and the pulsations of the abdominal aorta can also just be felt in thin people.

Umbilical region

Pain from intestinal obstruction, e.g. in acute appendicitis, could be referred to the area around the umbilicus. Pain and tenderness from disease of the transverse colon are also located in the umbilical region. The transverse colon is extremely variable in position, sometimes reaching down to the suprapubic region. Tumours of underlying structures and pulsations from the abdominal aorta are palpable here.

Suprapubic (hypogastric) region

Pain and tenderness from the lower bowel, e.g. descending colon and anal canal, bladder and uterus, and, sometimes, the fallopian tubes, are referred to this region. Enlargement or tumours of the pelvic organs, e.g. bladder and uterus, are palpable here.

Left and right hypochondrium

The spleen is situated behind the left lower ribs. Splenic tenderness and enlargement are felt in the left hypochondrium, although the spleen has to be enlarged to more than three times its normal size to be palpable. The liver and gall bladder are behind the rib cage on the right. An enlarged or tender liver and gall bladder may be palpated in the right hypochondrium.

Left and right lumbar region

The lumbar regions refer to the ‘flanks’. Normally, the kidneys lie deep against the posterior abdominal wall and are not palpable. The lower poles of enlarged kidneys may be felt in the lumbar regions. The right kidney is usually lower than the left one. Posteriorly, the angles formed by the ribs and the spine are the renal angles where maximal renal tenderness may be felt when the kidneys are dilated or inflamed. The ascending colon may be palpable in the right lumbar region and the descending colon in the left.

Left and right iliac fossa (inguinal region)

Pain and tenderness in the left iliac fossa could be related to problems with the descending or sigmoid colon, whereas signs in the right iliac fossa signify disease of the appendix, caecum or ascending colon. Deep iliac fossa pain may relate to fallopian tube disease. Masses in either iliac fossa are suspicious of underlying tumours, but sometimes a loaded colon or impacted faeces may be palpable.

The pulsations of the femoral artery are easily felt at the midpoint between the anterior superior iliac spine and the pubic symphysis along the inguinal ligament. A weakness in the inguinal canal can cause some abdominal contents to be forced through this potential weakness in the inguinal region (hernia) when the intra-abdominal pressure is significantly raised, as in coughing and lifting heavy weights. This manifests as palpable ‘bulges’ medial to the femoral artery when a patient is asked to cough, particularly when standing.

Lubrication

The water and mucus in saliva act as lubricants that aid the movement of the tongue to facilitate speech and swallowing of food. You may have noticed that it is difficult to talk when your mouth is dry. Swallowing a number of dry biscuits is also difficult unless they are accompanied by a drink.

Protection

The presence of food debris in the warm and wet environment of the mouth provides ideal conditions for bacterial growth and division. The mouth is protected from metabolic acids produced by bacteria by the buffering action of bicarbonate, phosphate and mucus in saliva. The saliva is saturated with calcium salts at neutral pH, so that the calcium in the teeth does not dissolve. However, calcium from the teeth will dissolve and the formation of dental caries will occur if the pH falls to 5.5, once saliva flow has been reduced after a meal. The presence of protein in saliva forms a protective coat on the teeth surface to reduce the adherence of bacteria and to act as a barrier to acid. In addition, bacterial growth is limited by

• Lysozyme, an enzyme responsible for breaking down bacterial cell walls

• Lactoferrin, an iron-chelating agent that binds iron to prevent its use by some bacteria requiring iron for growth

• Secretory immunoglobulin A, derived from plasma cells, which provides immunity against bacteria and viruses.

Large volumes of alkaline saliva are produced before vomiting. The alkali neutralises the gastric acid and inactivates the enzyme pepsin when it enters the oesophagus and mouth during vomiting.

Digestion

The digestive function of saliva is to dissolve food so that the chemical constituents can stimulate the taste buds and to begin chemical digestion of carbohydrate and fat. Saliva contains an α-amylase or ptyalin, which starts the digestion of starch by hydrolysing α-1,4 glycosidic bonds to produce maltose, maltotriose and oligosaccharides known as α-limit dextrans (see Fig. 15.3 ). Salivary amylase is active over the pH range of 4–11 and has an optimum pH of 7. Chewing mixes the saliva with food. The amylase present inside a bolus of swallowed food continues its activity in the stomach until the acid in the gastric secretions penetrates the bolus. Up to 75% of starch digestion may occur in the stomach before amylase is destroyed by gastric acid.

Salivary glands present on the tongue secrete a lingual lipase that digests fat. This enzyme is also active in the stomach and intestine.

Organic constituents

These consist of

• Amylase (ptyalin)

• Lipase

• Kallikrein

• Lysozyme

• Mucus

• Immunoglobulin A

• Lactoferrin

• Blood group antigens, e.g. A and B.