Part 2 

Body systems and their principal diseases 

3.Gastrointestinal and liver diseases

Gastrointestinal problems are a frequent cause of GP consultations and comprise about 15-20% of the primary care workload. In the West, refined diets and food additives have been implicated in many gastrointestinal and systemic diseases, problems that are exacerbated by the increasing consumption of manufactured and convenience foods. Repeated health scares have led to a proliferation of diets that are often faddist and of dubious nutritional value, and there is a plethora of sometimes conflicting and confusing dietary advice. Intensive farming and increasing technology in the kitchen, e.g. frozen foods, refrigeration and microwave ovens, have combined with a generally poor understanding of basic food hygiene to produce an apparently inexorable rise in the incidence of ‘food poisoning’ in the UK.

  Meanwhile in the Third World, poverty, population increase, crop failure, poor hygiene, political instability and wars have caused massive malnutrition and starvation and led to refugee problems.  These  factors  have  created  the  conditions  for  epidemics  of  gastrointestinal  diseases. Underlying all of this are the endemic helminth, protozoal, bacterial and viral infections that are already responsible for many intractable public health problems.

Gastrointestinal anatomy and physiology

Overall review

This chapter reviews briefly the anatomy of the 

digestive tract to help associate symptoms with 

organs. This leads to a synopsis of gastrointestinal 

physiology as a basis for appreciating the patho-

physiology underlying the principal diseases and 

disorders,  and  so  to  their  management.  More 

detail about particular organs and their physi-

ology is provided later, in the sections dealing 

with diseases of the individual organs.

The  gastrointestinal  tract  (GIT,  alimentary 

tract, gut; Figure 3.1) consists of an irregular tube 

some 6 m long, extending from the mouth to 

the anus. Accessory organs include the teeth, the 

tongue, the salivary, gastric and intestinal glands, 

the liver and gallbladder, and the pancreas.

For the purposes of this text, we will distinguish three groups of organs:

•  The upper GIT, which includes the mouth, 

oesophagus and stomach.

•  The   lower   GIT,   which   comprises   the 

duodenum, jejunum, ileum, colon, rectum

and anus.

•  The  liver,  gallbladder  and  pancreas  (the

accessory organs).

Upper gastrointestinal tract

Food taken into the mouth is mixed with saliva 

to  form  a  plastic  mass.  The  salivary  glands 

secrete  about  1 L  of  fluid  daily;  this  contains

a lubricant  (mucin) and the polysaccharidase 

enzyme, salivary amylase.

The food bolus is then swallowed and trans-

ferred rapidly via the oesophagus into the stom-

ach. The stomach is joined to the oesophagus at 

the gastro-oesophageal junction, where there is 

a poorly defined lower oesophageal sphincter 

(LOS).

The stomach is a highly distensible J-shaped 

organ that varies enormously in size and shape 

depending on its food content. The stomach 

secretes a gastric juice containing hydrochloric 

acid and pepsinogen, plus small amounts of gas-

tric lipase. The acid converts pepsinogen into the 

proteolytic enzyme pepsin, provides the low pH 

suitable for its action and has a direct digestive 

function by hydrolysing some foods. The lipase 

splits short-chain triglycerides into glycerol and 

fatty acids. Infants, but not adults, also secrete 

the enzyme rennin (not to be confused with the 

renal enzyme, renin), which coagulates milk and 

so prevents too rapid a passage of liquid milk out 

of the stomach.

Gastric secretion is under complex nervous 

and hormonal control (see below). There are 

three phases of acid secretion:

•  Cephalic, arising centrally and mediated by 

vagal stimulation (appetite arousal).

•  Gastric, which occurs when food stretches 

the stomach and stimulates the stretch recep-

tors and chemoreceptors in the gastric walls. The latter respond to the rise in pH when 

food enters the stomach.

•  Intestinal, initiated by the passage of acid 

chyme (see below) into the duodenum, which 

provokes intestinal (local) gastrin release.

  The presence of food in the small intestine 

additionally provokes a nervous (enterogastric) 

reflex via the vagus nerve, which inhibits gastric 

secretion,  and  a  further  moderate  inhibiting 

effect is produced by small bowel secretion of 

secretin and cholecystokinin (CCK). The pur-

poses of these mechanisms are probably to delay 

further gastric emptying into an already full 

small intestine and to inhibit unnecessary gastric 

secretion  and  digestion,  once  digestion  is 

focused on the intestinal phase.

 Between meals, the stomach normally secretes only a few millilitres per hour of slightly alkaline mucus (which protects the gastric mucosa from the acid and pepsin), although this is insufficient to neutralize residual gastric acid, so the basal pH remains acidic. Strong emotional stimuli may cause secretion of about 50 mL/h of gastric juice containing acid and pepsin, in the absence of 

food, via the cephalic mechanism.

Peristaltic waves ripple along the walls of the 

stomach every 15-30 s, macerating the food and mixing it with the gastric juice, finally producing 

a fluid called chyme. The presence of caffeine 

and partially digested protein stimulates the G 

cells in the pyloric antrum, the region of the 

stomach just before the pyloric sphincter, to 

liberate the hormone gastrin. Gastrin is carried 

via the blood and causes contraction of the LOS 

and the production of more gastric juice.

Over some 2-6 h, the entire content of the 

stomach  is  gradually  emptied  into  the  duo-

denum via the pyloric sphincter. The gastric 

residence  time  depends  on  several  factors, 

including the nature of the stomach contents, 

being  shortest  for  meals  rich  in  carbohydrate 

and longest for those rich in fats. Gastric emp-

tying depends on peristaltic waves, more pow-

erful than those that mix the stomach contents, 

which begin in the middle of the stomach and 

create a relatively high pressure, overcoming the 

resistance of the pyloric  sphincter  and  forcing 

out  about 5 mL  of  chyme  with  each  wave. 

Emptying  is  also influenced by feedback from 

the duodenum: in particular, fats in the duode-

num  delay  gastric  emptying.  Little  nutrient 

absorption occurs from the stomach, but salts, 

alcohol and some acidic drugs, being unionized 

in the acid environment and so lipophilic, may 

be absorbed there.

Lower gastrointestinal tract

The chyme is discharged into the first part of the 

small intestine, the duodenum, a tube about

25 cm  long  that  curves  around  the  head  of 

the pancreas to merge into the jejunum. The 

duodenal mucosa secretes alkaline mucus that 

starts to neutralize the acid chyme and release 

a   different   set   of   digestive   enzymes.   The 

duodenum also receives about 1.5 L daily of 

pancreatic juice, and bile from the gallbladder, 

via the common bile duct and the ampulla of 

Vater (Figure 3.3). Chyme also stimulates the 

production  of  the  hormone  secretin,  which 

stimulates the production of alkali in the pancre-

atic juice. The production of pancreatic amylase, 

lipase, deoxyribonuclease and ribonuclease, and 

proteolytic  enzymes,  is  stimulated  by  signals 

from the vagus nerve and the small intestinal 

release of CCK, due to the presence of partially 

digested fats and proteins. The CCK stimulates

the release of an enzyme-rich pancreatic juice and of bile from the gallbladder.

The jejunum is about 1.5 m long and merges 

with the final part of the small intestine, the 

ileum  (3 m), which joins the large intestine 

(colon) (1.5 m)  at  the  ileocaecal ‘valve’, 

although it is unclear whether any histological 

structure  or  effective  valve  actually  exists  at 

this location. The walls of the small intestine are 

covered with numerous small villi: finger-like 

projections, each about 1 mm long, that enor-

mously increase the surface area of the small 

intestine (Figure 3.2(c)) and thus facilitate the 

absorption of nutrients and drugs.

Rhythmic contractions of the small intestine mix  the  chyme  with  the  intestinal  digestive secretions, and peristaltic waves gradually propel the mixture through the intestinal length.

Up to 3 L of intestinal juice is secreted daily. 

This  contains  mucus,  digestive  enzymes  and 

bicarbonate, giving a pH of about 7.6. To this is 

added about 1.5 L daily of an alkaline, enzyme-

laden pancreatic juice that is discharged into the 

duodenum via the pancreatic duct (Figure 3.3). 

The enzymes in the pancreatic juice convert 

proteins and protein fragments, fats, carbohy-

drate residues and nucleic acids into smaller, 

absorbable molecules.

The large intestine comprises the caecum and 

colon, and terminates with the rectum and anal 

canal. The caecum is a 6 cm pouch located in 

the right iliac region (Figure 3.1(c)), to which the 

vermiform appendix is attached. The latter is 

an 8-cm blind tube for which no proven func-

tion exists, though it may have some protective 

lymphoid  role.  Infection  of  the  appendix 

(appendicitis)  is  the  most  common  surgical 

emergency. The caecum merges into the ascend-

ing colon  (15 cm long), which turns sharply 

downwards and to the left at the right colic 

flexure to form the transverse colon (50 cm), 

which is concave upwards and ends at the left 

colic (splenic)  flexure  where  it  turns  down 

sharply to form the descending colon (25 cm).

The final part of the colon consists of two S-

shaped tubes: the sigmoid colon, which is a loop 

(40 cm) in the left iliac region, merging into the 

rectum (12 cm). The latter is curved, at first back-

wards and upwards and then finally downwards 

and forwards. At its end, the rectum narrows to join the anal canal (3.5 cm). The upper part of 

the anal canal has up to 10 longitudinal folds (the 

anal columns), and is surrounded by the muscles 

of the internal anal sphincter, which hold the 

anal columns together very tightly in order to 

prevent faecal leakage. The terminal part of the 

anal canal, the anus, blends into normal skin. For 

greater security and control, the entire length of 

the anal canal is enclosed by the external anal 

sphincter: this consists of striated muscle that is 

under  voluntary  control,  unlike  the  internal

 sphincter,  which  is  composed  of  involuntary circular smooth muscle.

Regions of the abdomen

The abdominal surface is thought of as being 

divided into nine regions, to make it easy to 

describe the location of organs or symptoms 

(Figure 3.1(c)). Comparing Figures 3.1(a), (c) and

(d) shows the regions under which the various organs  lie,  and  these  locations  are  further 

outlined in Table 3.1.

General histology of the gastrointestinal 

tract

The whole of the GIT, apart from the mouth, has 

a similar basic tissue arrangement. A generalized 

cross-section of the gut is illustrated in Figure

3.2(a), which shows that there are four basic 

layers (tunics).

Tunics

The most important of these tunics, from the 

point of view of digestion, is the inner lining, 

the mucosa, which itself consists of three layers. 

The  epithelium  is  in  contact  with  the  gut 

contents, has a protective function, and changes 

somewhat  in  character  in  the  different  areas 

of  the  gut.  Although  continuous  with  the 

epidermis (see Chapter 13) at both ends, the 

epithelium is not keratinized, and permits a vari-

able degree of absorption of foods and drugs to 

occur, depending on the precise site and local 

conditions. The lamina propria contains glan-

dular epithelium that secretes digestive enzymes 

and adjuncts. It also contains the blood vessels 

and  lymphatics,  bound  by  loose  connective 

tissue, that carry absorbed substances into the 

circulation and are distributed to the tissues.

 There are also lymph nodes that provide foci for 

protection against infective agents (see Chapter

2). The muscularis mucosae contains visceral smooth muscle, the tone of which throws the 

mucosa into small folds, providing for the consid-

erable changes in volume that are required to 

respond to food intake while maintaining a large surface area for digestion and absorption.

The submucosa consists mostly of loose con-

nective tissue, but has a rich blood supply and also contains glands, and nerve plexuses that 

provide  the  autonomic  nerve  supply  to  the muscularis mucosae.

The muscularis throughout most of the gut 

consists of an inner, transverse circular layer of 

smooth muscle and an outer longitudinal layer. 

Contraction of these muscles tends to break 

down the food masses, and causes the food to 

mix with the digestive juices, after which it is 

propelled  by  peristalsis  along  the  GIT.  The 

mouth, pharynx and oesophagus have a more 

complex, partly striated, musculature.

Within the abdomen, the gut is surrounded by 

the folds of the peritoneum, which form the 

outer layer of the gut, the serosa. These folds 

support the viscera, hold the organs in relation 

to each other and to the abdominal wall, and 

carry the blood, nerve and lymphatic supplies to 

the gut. Where these supplies enter the gut wall 

the tunics are structurally weakened, and this 

may result in pouches (diverticula, p. 124) being 

formed under pressure from within the lumen. The part of the peritoneum that supports the 

small intestine is the mesentery, the mesocolon 

similarly supporting the large intestine. Other 

important peritoneal folds are the falciform lig-

ament that attaches the liver to the abdominal 

wall and the diaphragm, the lesser omentum 

that suspends the stomach and duodenum from 

the liver, and the greater omentum, a large fold 

of tissue that hangs like an apron in front of 

the intestines. The greater omentum contains 

numerous lymph nodes and is the principal 

repository of abdominal fat. The large surface 

area and rich blood supply of the peritoneum 

make it valuable for peritoneal dialysis in renal 

failure (see  Chapter 14).  Peritoneal  infection 

(peritonitis)  is  always  extremely  dangerous 

because the peritoneum is in contact with all the 

abdominal organs, which may be infected sec-

ondarily, and because it has a large surface area 

for the absorption of microbial toxins.

 Stomach

The mucosa of the stomach is highly specialized. 

It contains many minute openings, which are 

the apertures of the gastric glands (Figure 3.2(b)). 

These glands are lined with four types of secre-

tory cells. The zymogenic (chief) cells secrete 

pepsinogen, which is converted into pepsin by 

the hydrochloric acid produced by the parietal 

cells.  The  parietal  cells  also  secrete  intrinsic 

factor, a glycoprotein that binds vitamin B12 

(extrinsic factor) from the food and transports it 

to specific ileal mucosal receptors, where it is 

liberated  into  the  cells.  The  intrinsic  factor 

remains in the gut lumen and is recycled. The 

mucous cells secrete an alkaline, bicarbonate-

laden mucus which, together with other factors 

(see Figures 3.8 and 3.10), protects the mucosa 

from  the  acid  and  pepsin  and  also  further 

moistens and lubricates the food.

Small intestine

The mucosa of the small intestine (Figure 3.2(c)) 

has  many  circular  folds  and  numerous  villi, 

which  carry  many  more  minute  microvilli 

projecting from their surface. This arrangement 

produces an enormous surface area for the secre-

tion of digestive enzymes and the absorption of 

food. The core of each villus contains specialized 

lymphatic  vessels (lacteals)  surrounded  by  a 

network of arterioles and venules. Between the 

bases of the villi are the crypts of Lieberkühn, 

which contain zymogenic (enzyme-producing) 

cells. The epithelial cells are formed at the bases of 

the crypts and migrate upwards over a period of 

about 3-4 days, after which they are shed. Thus, 

the epithelium is being continuously regener-

ated,  so  that  any  acute  pathological  process 

affecting it, e.g. inflammation or infection, is 

inherently  self-limiting  unless  the  damage  is 

severe or becomes prolonged. However, this rapid 

cell  turnover  makes  the  gut  highly  sensitive 

to  radiotherapy  and  cytotoxic  chemotherapy, 

which may cause significant damage.

In  addition  to  the  lymphatic  vessels,  the 

lamina propria of the small intestine contains 

numerous  immunologically  active  cells,  e.g. 

plasma cells, lymphocytes, macrophages, mast 

cells,  etc.,  solitary  lymph  nodes  and  Peyer’s 

patches (aggregates  of  lymphatic  nodules). 

These are concerned with the immunological 

defence of the gut and are more numerous in the 

ileum than in other regions. Specialized micro-

fold cells (M cells) above the Peyer’s patches 

permit the ready localization of antigens that 

stimulate the local cloning of B cells (see Chapter

2). The latter secrete IgA (secretory Ig) into the 

gut lumen, providing surface protection against 

orally  ingested  infective  agents  that  are  not 

killed by the acid gastric juice, the alkaline pan-

creatic juice duodenum and the surface activity 

of the bile.

Large intestine

The colon wall differs from that of the small 

intestine. It has no villi, and so little nutrient-

absorbing function, although some amino acids 

and vitamins are absorbed there. It also has pits, 

which are the openings of tubular glands that

extend the full mucosal thickness. The surface 

of the mucosa is comprised of simple colum-

nar epithelium that extends into the glands. 

However,  the  glandular  epithelium  contains 

numerous mucus-secreting goblet cells. There 

are isolated lymphatic nodules, which form part 

of  the  immune  system.  The  colon  has  five 

principal functions:

•  To complete the digestion of residual food-

stuff. Although the colon does not secrete

enzymes, it harbours bacteria that ferment 

carbohydrate, convert amino acids to indole 

and skatole (which give faeces its character-

istic odour) and bilirubin  to urobilinogen. 

Bacterial activity also produces some of our 

daily intake of B vitamins and vitamin K and 

breaks down some prodrugs, e.g. sulfasalazine 

and olsalazine (p. 121).

•  To  secrete  mucus,  which  lubricates  faecal 

passage and protects the mucosa.

•  To convert the fluid ileal contents into faecal 

paste by mixing and the reabsorption of water

and electrolytes.

•  To absorb water, electrolytes and vitamins. 

•  To   store   the   faeces   until   defecation   is

convenient.

Nutrient breakdown and absorption

Proteins

The digestion of protein begins in the stomach 

where pepsin (under acidic conditions) converts 

proteins into peptides, which then stimulate the 

pyloric antrum to secrete gastrin. The gastrin 

enhances the secretion of histamine, and so of 

acid, from the parietal cells, and of bicarbonate-

laden mucus. Discharge of the acid chyme into 

the duodenum stimulates further gastrin release, 

which in turn promotes the release of bile (by 

relaxing the sphincter of Oddi), and stimulates 

the pancreas to secrete bicarbonate.

The presence of dietary fats in the small intes-

tine  triggers  the  secretion  of  CCK (pancre-

ozymin, cholecystokinin), leading to pancreatic 

pro-enzyme release, e.g. trypsinogen, and bile 

ejection  from  the  gallbladder.  Vagal  acetyl-

choline  is  also  involved.  The  trypsinogen  is 

converted into active trypsin, which in turn converts  other  pancreatic  pro-enzymes  intolipoid materials are solubilized and emulsified by

active  proteolytic  enzymes.  These  produce 

absorbable dipeptides and free amino acids, and longer-chain peptides. These longer peptides are finally converted into amino acids by specific peptidases in the cells of the microvilli or the 

epithelium, before their systemic absorption via specific active transport mechanisms.

Thus there is a complex hormonal and neu-

ronal  positive  feedback  mechanism,  which 

responds to the presence of food in the gut, and which controls the secretion and activation of appropriate enzymes (see Figure 3.8).

Carbohydrates

The digestion of carbohydrates starts in the mouth 

with salivary amylase, which continues to act 

until stopped by the low gastric pH. However, 

carbohydrates are mostly digested to monosac-

charides in the upper small intestine, first by 

pancreatic  amylase  and  finally  by  intestinal 

saccharidases. The resultant glucose, fructose and 

galactose are absorbed into the villi by sodium-

dependent active transport systems. Deficiencies 

of maltase, sucrase and lactase enzymes cause accu-

mulation  of  the  corresponding  disaccharides, 

which pass unabsorbed to the colon, producing 

an osmotic diarrhoea. Such deficiency may be 

congenital  or  may  temporarily  follow  severe, 

prolonged  diarrhoea.  Also,  nucleic  acids  are 

converted into nucleotides and nucleosides by 

cleavage of their pentose-phosphate chains.

Fats

Dietary lipids consist principally of triglycerides, 

plus small amounts of cholesterol and its esters 

and phospholipids. Lipid digestion occurs pre-

dominantly in the small intestine after emulsifi-

cation by bile salts. The resultant fat globules are 

hydrolysed, primarily by pancreatic lipase and, 

being insoluble in water, can be hydrolysed only 

at the globule surface: emulsification is essential 

to provide an adequate surface area for hydrol-

ysis to proceed effectively. Bile salts are also 

required for the absorption of fat-soluble vita-

mins (A, D, E, K) and to enhance vitamin uptake.

Pancreatic  lipase  hydrolyses  triglycerides  to 

monoglycerides plus fatty acids. All of these

the bile salts before they are absorbed into the 

villi.

Following hydrolysis, the resultant monoglyc-

erides and free fatty acids, which are solubilized 

in micelles, partition into the lipid membranes 

of the microvilli and are readily absorbed. The 

bile salts are recycled by enterohepatic circula-

tion and reused. Cholesterol esters are similarly 

solubilized, and are then hydrolysed by choles-

terol  esterase:  without  bile  salt  solubilization 

no  cholesterol  whatsoever  is  absorbed.  Thus, 

diseases  reducing  gallbladder  and  pancreatic 

activity may result in only 30-50% of dietary fat 

being absorbed. The resultant fatty stools are 

pale, soft and particularly foul-smelling (steator-

rhoea). Very short gut transit times can cause 

similar effects.

After absorption, the monoglycerides and fatty 

acids are reconstituted into triglycerides in the 

mucosa. Globules of these, plus cholesterol and 

phospholipids, are coated with protein to yield 

chylomicrons,  which  pass  into  the  central 

lacteals of the villi (Figures 3.2(c) and 3.4) and 

into the general circulation via the portal vein 

and thoracic duct. A lipoprotein lipase produced 

by capillary endothelial cells completes digestion 

of the chylomicrons. The glycerol is metabolised 

and the fatty acids are absorbed into the liver 

and  fat  cells  of  adipose  tissue,  where  they 

combine with glycerol produced in the cells to 

reform triglycerides.

Bile salts are highly conserved,  95% being 

reabsorbed in the distal ileum; thus ileal diseases, 

e.g. Crohn’s disease (p. 114), may lead to a fail-

ure to reabsorb bile salts. Bile salts are highly 

irritant, and when they reach the colon are part-

ly responsible for the severe diarrhoea of this 

condition. Indeed, bile salts used to be used as 

laxatives.

Fluid and electrolyte absorption and conservation

Sodium

Each day, about 25 g of sodium is secreted into 

the gut, and a further 5 g is ingested with food: 

this total of 30 g represents about 15% of the total 

body sodium. Active sodium resorption occurs in 

the upper jejunum, where it is associated with monosaccharide and amino acid absorption, and in the ileum and ascending colon. Sodium trans-

port is usually accompanied by water, except in the kidney (see Chapter 14), so almost complete water resorption also occurs, especially in the distal ileum and in passage through the colon 

(Table 3.2). This means that only about 100 mL of water is lost daily in the faeces.

Because the absorption of sodium from the 

small intestine must be accompanied by water,

 this  mechanism  is  used  to  treat  dehydration 

by  oral  rehydration.  Sodium  absorption  is 

enhanced by glucose (facilitated active trans-

port), so water absorption is also enhanced. This 

is the rationale behind the use of oral rehydra-

tion  salts (containing  glucose)  and  similar 

proprietary products for the treatment of fluid 

loss caused by severe diarrhoea and vomiting.

The ileal discharge into the caecum is always fluid  or  semi-fluid (about  1 L/day),  compared with  the  semi-solid  stools  in  the  colon,  andAbsorption sites for nutrients and drugs

these  differences  have  implications  for  the

management of patients with stomas (p. 133).

Calcium

Absorption of calcium occurs in the small intes-

tine, being dependent on the presence of the 

active form of vitamin D (1,25-dihydroxychole-

calciferol, calcitriol) and a specific calcium-binding 

protein. Although still described as a vitamin, 

1,25-dihydroxycholecalciferol (see Figure 3.21) is 

actually a hormone that controls calcium home-

ostasis, primarily in association with parathyroid 

hormone (PTH). Vitamin D synthesis and calcium 

absorption  are  regulated  principally  by  PTH, 

although  other  hormones  (i.e.  calcitonin  and 

glucocorticoids),  and  sex,  growth  and  thyroid 

hormones are also involved.

Iron

In the UK, the average daily intake of iron is 

about 20 mg, only 2 mg of which is absorbed (in 

the duodenum and jejunum), although absorp-

tion  increases  in  iron-deficiency  states.  The 

average daily requirement of iron for erythro-

poiesis is about 20 mg. Because there is a daily 

faecal  iron  loss  of  about 750 lg  (plus  about

2.5 mg/month in menstruation), it is clear that 

the iron content of the body is finely regulated, 

absorption being linked closely to needs. Most of 

the iron liberated by the breakdown of Hb and 

other molecules is conserved. Some factors that 

affect iron absorption are given in Chapter 11 

(Table 11.2).

Potassium

The average dietary intake of potassium is about

80 mmol/day, and a further 40 mmol is excreted 

into the small intestine in the intestinal juice. As 

only about 10 mmol/day is lost in the faeces, 

about 110 mmol/day is absorbed in the ileum 

and colon. Diarrhoea and vomiting may cause 

substantial losses of potassium (and sodium), so 

fluid and electrolyte replacement is vital if these 

conditions are severe or prolonged. Although 

some  degree  of  potassium  loss  occurs  with 

long-term diuretic use, especially with thiazide 

diuretics,  oral  potassium  repletion  is  rarely 

indicated (see Chapters 4 and 14).

Some 90% of nutrients are absorbed in the small 

intestine, the remainder being absorbed in the 

stomach and large intestine. Absorption may be 

by processes of active transport (e.g. amino 

acids, sodium, potassium, calcium and iron), or 

of diffusion (e.g. water, chloride and fats). Fruc-

tose and some other nutrients are absorbed by 

the energy-independent process of facilitated 

diffusion, which is faster than simple diffusion. 

The transport of amino acids, glucose and galac-

tose is linked to that of sodium, the membrane 

transporter having binding sites for both sodium 

and  the  substance:  this  is  secondary  active 

transport.   Water   absorption   nearly   always 

accompanies that of solutes, as a ‘carrier’, and it 

moves freely, following osmotic gradients.

Whether or not substances (including drugs) 

are  absorbed  may  depend  crucially  on  their 

lipophilicity and, for some, on their ionizability 

(pKa). Generally, lipophilic substances will dis-

solve in the lipoid villus membrane and then be 

released inside the cell, but the pKa of an ioniz-

able substance and the local pH will determine 

whether that substance is absorbed or not.

Thus,  for  example,  aspirin  is  unionized 

(lipophilic) in the acid gastric juice and so will be 

absorbed into the gastric mucosa. Once inside 

the cells (internal pH about 7.4) it ionizes and is 

unable to diffuse out, and so is concentrated 

there. This property accounts in part for the 

ulcerogenic  property  of  aspirin  and  related 

NSAIDs.

Water-soluble substances and small chylomi-

crons  enter  the  mucosal  blood  and  then  the 

portal vein and so are delivered direct to the 

liver (Figure 3.4),  where  they  are  processed 

before discharge into the systemic circulation. 

This,  together  with  any  transformation  that 

occurs during absorption, is presystemic (first-

pass)  metabolism.  Although  this  occurs  with 

many types of absorbed compounds, the term 

is usually applied to drugs and the process may 

be very important with some of them, reduc-

ing  or  enhancing  their  bioavailability.  Thus 

with  organic  nitrates (e.g.  GTN)  and  propra-

nolol, high oral doses must be given to allow 

for that lost in presystemic metabolism, while 

the dopa-decarboxylase inhibitors benserazide or carbidopa  are  co-administered  with  levodopa specifically to prevent its mucosal and hepatic metabolism.

Because presystemic metabolism is reduced in 

the elderly and in liver disease, doses of drugs 

that have a high ‘first-pass extraction rate’ (i.e. 

are extensively metabolized in their first pass 

through the liver) may have to be reduced in 

such patients. For example, with propranolol the 

plasma concentration may be doubled in the 

elderly if the dose is not reduced. An alternative 

procedure is to avoid the portal circulation, and 

so  bypass  presystemic  metabolism,  by  giving 

the drug buccally (e.g. GTN), transdermally (e.g. 

GTN, hyoscine (scopolamine) and sex hormones), 

or parenterally, if that is practicable or desirable. 

When  drugs  are  formulated  as  prodrugs  to 

enhance absorption, we depend on metabolism 

to liberate the active form.

The larger chylomicrons are unable to enter 

the bloodstream directly and are carried in the 

lymphatic circulation via the thoracic duct, dis-

charging into the blood at the subclavian vein 

(Figure 3.4).

Investigation

Only  the  common  general  investigations  are described here. More specific tests are dealt with under the diseases to which they apply.

History

As usual, it is important to obtain a good history 

and to listen to patients and observe their appear-

ance and behaviour carefully. Food and the GIT 

are  powerfully  associated  with  emotional  and 

social attitudes, and public misconceptions are 

common. Attention to these aspects may provide 

important  clues  to  patient  understanding,  to 

social attitudes and emotional state, all of which 

may have a bearing on the interpretation of the 

information obtained.

It has been demonstrated that it takes only

5 min to obtain a good gastrointestinal history 

and, following this and an examination, a clini-

cian will have about 80% of the information

required for a probable diagnosis. The principal points to note are outlined in Table 3.3.

It is important for community pharmacists to 

be able to identify the signs and symptoms that 

may indicate the more serious gastrointestinal 

diseases, and to determine the urgency of treat-

ment or referral, because they are often asked to 

advise on the treatment of conditions causing 

apparently minor symptoms. Specific symptoms 

and signs will be discussed under the various 

organs and diseases.

Imaging

Radiology

Plain X-rays of the abdomen are of little value 

in investigating most gastrointestinal diseases. 

However, they can be useful in investigating 

acute conditions, when they will show accumu-

lation of air, toxic dilatation of the intestine and 

the presence of accumulated fluid (see Figure

3.15).

Barium contrast studies

Using fine suspensions of radio-opaque barium 

sulphate, these were the mainstay of investiga-

tion for many years, including the following:

•  Barium swallow, to visualize the oesophagus 

or to demonstrate refluxing of gastric contents. 

•  Barium meal, to examine the stomach and

duodenum. This is often combined with a 

small-bowel investigation, i.e. ‘barium meal and follow-through’, to visualize the gross 

anatomy of the small intestine, particularly the terminal ileum.

•  Barium enemas. Barium sulphate is intro-

duced into the empty large bowel rectally.

This permits visualization of the entire colon and, usually, the terminal ileum, but not the rectum. A small-bowel enema uses a large 

volume of dilute barium suspension, intro-

duced directly into the duodenum via an oral catheter.  It  provides  more  detailed  infor-

mation on areas of the small bowel that are suspicious on the follow-through.

•  Double-contrast   techniques   are   usually 

required for satisfactory visualization of the 

stomach,  duodenum  and  large  bowel.  A barium meal is followed by introducing a gas 

(carbon dioxide in the stomach, by giving 

bicarbonate; air in the colon) to distend the 

organ and push the barium sulphate into and 

around lesions of the wall (see Figures 3.12 

and 3.15).

Fluoroscopy

Direct real-time inspection of an X-ray image on 

a sensitive screen (nowadays a video monitor fed 

from an image intensifier to reduce the radiation

 dose to the radiologist) is especially useful for investigating disordered gut motility. The occur-

rence of gastro-oesophageal reflux (p. 82) can be observed directly.

Computed tomography (CT scanning)

This  is  a  computer-enhanced  X-ray  technique 

that  provides  views  of  a  succession  of  thin 

‘slices’ of tissue, but with much greater detail 

and contrast than conventional radiography. Its principal use in gastroenterology is to examine organs  outside  the  gut,  e.g.  the  liver  and 

pancreas. The radiation dose from CT is rela-

tively high but is less with the newer technique of ‘spiral CT scanning’, in which patients are moved longitudinally while the X-ray tube is rotated around them.

Nuclear magnetic resonance imaging (MRI)

The  MRI  scan  is  a  newer  technique  than  CT 

scanning and depends on atomic excitation by 

powerful magnets to produce images. It is capable 

of producing images of great detail and clarity, 

similar to CT though often superior to it. Both 

investigations are expensive, especially MRI, but 

have the advantage of being completely non-

invasive. Problems with current MRI machines 

are the need to confine patients in a small tunnel 

for  some  time,  during  which  they  must  be 

absolutely still, and the very noisy environment. 

Some  find  this  intolerable,  but  the  newer 

machines are less claustrophobic.

Endoscopy

Endoscopes permit direct viewing of organs and 

structures within the body. The older type is a 

rigid tube containing a plastic ‘light pipe’ that 

connects the objective and eyepiece lenses. A 

channel is provided for powerful illumination of 

the object to be visualized. This type of instru-

ment is now used only for proctoscopy and 

sigmoidoscopy (inspection of the rectum and 

terminal part of the sigmoid colon, respectively) 

and sometimes for the removal of obstructions 

from the oesophagus, e.g. fish bones.

The  fibre-optic  endoscope  (Figure  3.5)  is 

much more useful, and has revolutionized hos-

pital gastroenterological practice. The light pipe 

and illumination channel consist of a flexible 

glass  fibre-optic  bundle  that  transmits  light 

very  efficiently  and  is  completely  steerable 

through  the  gut.  Gastroscopes  permit  visual-

ization of the oesophagus, stomach and duode-

num, while colonoscopes provide views of the 

rectum, the whole of the colon, and the terminal 

ileum.

There  is  an  increasing  trend  for  interven-

tional  endoscopy, in which  instruments are inserted through the tube and used to take biop-

sy samples and to carry out minor surgery. These 

include the removal of foreign bodies, gallstones 

and colonic polyps, and cautery or injection of 

sclerosant to arrest bleeding. Patients are first 

sedated with a benzodiazepine (e.g. diazepam, 

lorazepam, midazolam or temazepam), a procedure 

that has the advantage of producing amnesia, 

especially with lorazepam, so patients have little 

recollection  of  an  uncomfortable  procedure. 

Temazepam has a rapid onset of action and gives 

rapid recovery, patients being reasonably alert 

after about 2 h. Local anaesthetic throat sprays 

(see  Chapter 7)  are  used  occasionally  before 

gastroscopy.

Endoscopy is more invasive and uncomfortable 

than radiographic imaging and cannot be used 

for certain purposes (e.g. investigating refluxing), 

though it can show its effect on the oesophagus. 

Which technique is used will depend on patient 

suitability and the availability of facilities and 

local expertise.

Wireless capsule endoscopy uses a single-use miniaturized capsule, about the size of a large tablet, containing a light source, camera, wireless transmitter and battery. It is swallowed with 

water and transmits two images every second to a portable data recorder over an 8-h period. 

These are correlated with positional information from external abdominal sensors.

Capsule endoscopy gives good results in locat-

ing the source of obscure intestinal bleeding and 

has  been  shown  to  be  superior  to  flexible 

enteroscopy and radiography in the diagnosis of 

small bowel pathology. Although it does not 

provide  any  interventional  capability,  unlike 

flexible enteroscopy, it is non-invasive and so is 

useful as an early diagnostic tool that can avoid 

extensive investigation and point to the most 

appropriate  treatment.  However,  it  is  rather 

expensive.

Ultrasound

This technique, which uses computer analysis of ultrasonic reflections from internal organs, is 

completely non-invasive and non-stressful and is now used extensively. It can be used to visualize a variety of abdominal structures, especially the liver, gallbladder and biliary tree.

Stool examination

Stools are examined to look for:

•  The passage of blood. Large amounts in the 

upper  gut (÷100 mL)  become  obvious  as

melaena  (i.e.  black,  tarry  stools),  or  on 

microscopy,  while  smaller  amounts  not 

apparent visually are detected by the faecal 

occult  blood  test,  but  this  is  of  limited 

value because it yields a high proportion of 

false-positives.

•  Excessive  fat  (steatorrhoea)  or  undigested

food in suspected malabsorption syndromes

(p. 111).

•  Pathogens, by microscopy (especially protozoa, 

see Chapter 8), or stool culture.

Other investigations

The  standard  investigations  provide  valuable 

information about the possible origins of symp-

toms, as well as on the condition of patients and 

their progress. In cases of uncertainty the tests 

ordered  should  depend  on  the  provisional 

diagnosis, because specialized tests are usually 

expensive  and  may  not  be  readily  available. 

Further, the best yield of information comes from 

carefully targeted tests ordered on the basis of 

sound  clinical  evidence  from  the  history  and 

examination. Capsule endoscopy (see above) falls 

into this class, and examples of a few other special-

ized  gastroenterological  tests  are  given  below.

In developed countries, nutritional deficiency 

is rare and vitamin assays are unusual. However, 

vitamin assays may be carried out, for example 

in pregnancy (folate), strict vegans (vitamins B12,

D), anorexia (folate), liver and gallbladder dis-

ease (vitamins A, D), renal failure (vitamin D), 

alcoholism (B  vitamins)  and  malabsorption 

syndromes.

Examples  of  other  specialized  tests  in  gas-

troenterology  are  oesophageal  manometry  in 

achalasia (p. 87), jejunal biopsy in malabsorp-

tion (Figure 3.14), oral sodium amidotrizoate to 

locate  fast  gastrointestinal  bleeds,  and  radio-

labelled  erythrocytes,  to  locate  slow  bleeds. 

Radiolabelled leucocytes are used to locate foci 

of inflammation.

Disorders of the upper gastrointestinal tract

 Oesophageal disorders

Introduction

The principal oesophageal disorders are gastro-

oesophageal reflux disease, dysphagia  (diffi-

culty in swallowing), pain on swallowing and bleeding. These may caused by:

•  local problems within the oesophagus, e.g. 

infection, inflammation, stricture, ulceration

and malignancy;

•  a manifestation of generalized disease, e.g. 

oesophageal varices consequent on hepatic

disease, e.g. cirrhosis (p. 156), systemic scle-

rosis (see Chapter 12) and diabetes mellitus (see Chapter 9);

•  neuromuscular  dysfunction,  e.g.  achalasia, 

spasm, myasthenia gravis;

•  pressure from neighbouring organs, e.g. goitre, 

left atrial enlargement due to hypertension; 

•  anatomic changes, e.g. pregnancy or hiatus

hernia  (see  below),  causing  refluxing  of stomach contents into the oesophagus.

Gastro-oesophageal reflux disease

Definition and aetiology

Gastro-oesophageal reflux disease (GORD, GERD 

in North America) is caused by refluxing of 

stomach contents (occasionally with some bile, 

i.e. reflux oesophagitis), into the oesophagus, 

causing heartburn, which occurs in about 75% 

of cases. Heartburn is a retrosternal burning pain 

of variable severity that accounts for about 30% 

of all cases of dyspepsia, but refluxing can occur 

without producing symptoms. The oesophageal 

mucosa has little or no protection against the 

acidity and proteolytic activity of the gastric 

juice.  A  number  of  factors  may  reduce  the 

competence of the LOS, and so predispose to 

refluxing. These include:

•  fatty foods, including chocolate, which lubri-

cate the mucosa of the LOS and so facilitate

the reverse passage of stomach contents; 

•  excessive caffeine (coffee) consumption and

anticholinergic drugs, which relax the smooth muscle of the LOS;

•  excessive intra-abdominal pressure caused by, 

for example, poor posture, obesity, pregnancy; 

•  hiatus hernia (see below).

It is reported that the incidence of GORD is 

rising,  and  this  is  accompanied  by  a  rapid, 

worrying   increase   in   the   incidence   of 

oesophageal cancer. Up to 25% of duodenal ulcer 

patients from whom Helicobacter pylori has been 

eradicated (see below) may develop GORD.

About 50% of pregnant women suffer from 

heartburn  caused  by  raised  intra-abdominal 

pressure, reduced sphincter tone or a temporary 

hiatus  hernia (a  protrusion  of  the  stomach 

through the muscular diaphragm, Figure 3.6). 

Because the stomach is then subjected to abnor-

mal pressure differentials, and the muscles of the 

diaphragm no longer aid the sphincter action, 

this condition predisposes to refluxing, especially 

on bending forward.

A permanent hiatus hernia may be congeni-

tal or occur in early infancy, but is more usual in 

the middle-aged and elderly. Although many 

patients with demonstrable hiatus hernia are 

asymptomatic, or show symptoms other than 

heartburn, the presence of a hiatus hernia may 

aggravate refluxing. Similar symptoms may also 

occur in normal subjects without demonstrable 

refluxing and with an undamaged oesophageal 

mucosa,  resulting  from  an  abnormality  of 

oesophageal motility.

Causes of oesophageal damage other than refluxing

Oesophageal  damage  may  also  be  caused  by 

excessive   alcohol (spirits)   consumption   and 

candidiasis. Candidal infection may result from 

depressed immunity (e.g. by drugs, including inhaled   corticosteroids,   or   malignancy),   or 

broad-spectrum antibiotic treatment, especially 

in  debilitated  or  immunosuppressed  patients. 

Taking  tablets  or  capsules  while  lying  down, 

or without adequate fluid, may result in the 

medication being retained in the oesophagus 

and release of the drug there, causing local irrita-

tion or ulceration. This is a particular problem in 

elderly patients and with drugs such as potassium 

chloride, aspirin, indometacin and other NSAIDs, 

bisphosphonates (notably  alendronic  acid  and 

ibandronic acid), and some antibiotics.

It is not known precisely why smoking aggra-

vates symptoms, because it has several pharma-

cological effects that might be involved, but 

increased gastric acid production, gastric and oesophageal stasis and local irritation may all be implicated.

People with an abnormality that restricts the 

oesophageal lumen (e.g. oesophageal stricture), 

and enlargement of organs in the mediastinum 

(e.g.  aortic  aneurysm,  bronchial  carcinoma  or 

an  enlarged  left  atrium  consequent  on  mitral 

valve  disease),  are  also  at  risk.  The  left  main 

bronchus, the heart and the aortic arch are in 

close  proximity  to  the  oesophagus  and  may 

indent it or cause its deviation. Disease of medi-

astinal  organs  may  thus  increase  the  risk  of 

oesophageal restriction.

The relationship between oesophageal reflux, hiatus hernia and the occurrence of symptoms is illustrated diagrammatically in Figure 3.7.

Clinical features and diagnosis

The pain often occurs after food, which induces 

the secretion of gastric acid. An alcoholic or 

other ‘nightcap’ often causes nocturnal symp-

toms because lying down promotes refluxing 

from a consequently full, acid-laden stomach. 

However,  refluxing  does  not  usually  disturb 

sleep. Exertion, especially lifting heavy objects, 

or bending forward, may also produce refluxing. 

Occasionally the pain may be so severe as to 

mimic that of angina pectoris or myocardial 

infarction (see Chapter 4). There is an associa-

tion  between  refluxing  and  asthma,  because 

reflux causes vagally mediated bronchoconstric-

tion in about 50% of asthmatics, making asthma 

diagnosis  more  difficult.  The  symptoms  that 

may be associated with refluxing are outlined in 

Table 3.4.

Diagnosis is based on the clinical features and 

endoscopy, although there is a poor correlation 

between the severity of symptoms and endoscopy 

findings of mucosal damage or altered epithelial 

morphology. Negative endoscopy findings do not 

eliminate a diagnosis of GORD if the symptoms 

strongly suggest refluxing. The most appropriate 

diagnostic  category  in  this  situation  is  endo-

scopically negative reflux disease. GORD is the 

likely diagnosis if heartburn occurs on 2 days a 

week  or  more.  It  is  also  probable  if  upper 

abdominal or lower retrosternal symptoms are 

reliably  relieved  by  antacids.  Therapeutic  trial

of a high-dose proton pump inhibitor (PPI; p. 

86) is useful diagnostically.

However, other investigations that have been 

used widely in the past, e.g. fluoroscopic demon-

stration of reflux and production of symptoms on 

24-h oesophageal acid exposure, are unreliable.

Long-term complications

Although GORD usually occurs as a relatively brief acute attack of heartburn, repeated insult may cause oesophageal damage and chronic, 

persistent problems. Complications of chronic mucosal damage include:

•  pain on swallowing; •  ulceration;

•  haemorrhage;

•  oesophageal stricture causing dysphagia; 

•  perforation or malignancy (both are rare).

However, only about 5% of new patients with presumptive  GORD  are  likely  to  experience significant local complications.

Management: general aspects

The principal aim is to prevent reflux occurring 

and  so  prevent  damage  to  the  oesophageal 

mucosa and the development of complications. 

Drugs may also be used secondarily to relieve 

symptoms by reducing the acidity and irritancy 

of the refluxed gastric contents, and to improve the competence of the LOS. Drug treatment is 

primarily with PPIs. Antacids, H2-receptor antag-

onists (H2-RAs) and sphincter ‘strengtheners’ are 

also used but are less effective. General measures 

involving lifestyle modification, notably weight 

reduction to reduce intra-abdominal pressure, 

and raising the head of the bed by 15 cm to 

reduce  the  tendency  to  regurgitate  stomach 

residues, are often recommended but there is 

little evidence of benefit. However, they may be 

useful as adjuncts to effective pharmacotherapy.

All  treatments,  especially  the  antisecretory 

agents, may mask the presence of gastric malig-

nancy, so it is essential to exclude this possi-

bility  in  middle-aged  or  elderly  patients  with 

alarm  symptoms (p. 100)  by  gastroscopy, 

before initiating treatment aimed at the reduc-

tion of significant pain or if a trial of therapy is 

unsuccessful.

General measures

In the absence of good research-based evidence it  seems  sensible  to  avoid  factors  likely  to precipitate symptoms, i.e.:

•  take alcohol and caffeine-containing products 

only in moderation.

•  avoid:

-  large meals (especially at night), acid foods, 

alcohol;

-  a fatty diet and chocolate;

-  tight clothing or belts;

-  stooping and heavy lifting (bend the knees 

with the back straight);

-  drugs  that  may  reduce  LOS  pressure, 

e.g. diazepam, nifedipine, theophylline  and

antimuscarinics,  including  tricyclic  anti-

depressants;

•  stopping smoking may help some patients.

Feed thickeners improve symptoms in infants, 

as  does  sodium  alginate  in  children  under

2 years. Left lateral and prone positioning may 

help  to  reduce  symptoms  in  infants  under

6 months of age, but both of these positions 

increase the risk of sudden infant death relative to supine positioning.

These alone may be adequate in mild GORD, 

but good evidence for this approach is lacking. In 

view of this, patients should not attempt lifestyle 

modifications that impose excessive burdens.

Management: pharmacotherapy

The properties of the drugs discussed here are described under ‘peptic ulcer’ (p. 96), but aspects relevant to GORD are discussed below.

Antacids

Simple,    infrequent,    uncomplicated    reflux 

oesophagitis should be treated symptomatically, 

using antacids as symptoms occur. Suspensions 

are more effective than tablets but, for con-

venience  and  prompt  availability,  the  latter 

should be carried and sucked or chewed at the 

first sign of symptoms to minimize mucosal 

damage. They may also be sucked frequently 

between meals if symptoms tend to persist.

Alginate-antacid preparations.   These depend 

on the reaction between alginate, sodium bicar-

bonate and gastric acid to form a foam, stabilized 

with viscous alginate gel. An alkaline ‘raft’ of 

foamed alginate then floats on top of the gastric 

contents and may tend to inhibit reflux. The raft 

will also be the first part of the gastric contents 

to  be  pushed  into  the  oesophagus  if  reflux 

occurs, where it will form a protective alkaline 

coating. However, there is little evidence that 

this translates into significant clinical benefit 

compared with simple antacids, although some 

patients prefer them.

Most of the preparations in this class contain 

relatively  large  quantities  of  sodium,  and  so 

are unsuitable for patients with cardiovascular 

disease.   Some   preparations   are   now   being 

marketed  in  which  some  of  the  sodium  is 

replaced by potassium, but this may still cause a 

problem if patients are taking potassium-sparing 

diuretics.

If  symptoms  are  not  controlled  within

6 weeks, the patient should be investigated by X-ray (barium swallow) or endoscopy.

The strength of the alginate gel is reduced by 

aluminium and magnesium ions, so antacids 

containing  these  should  not  be  used  concur-

rently with alginates. Conversely, the addition of 

calcium ions is probably beneficial, because they 

react to produce a stronger calcium alginate gel, 

twice  as  much  of  which  is  retained  in  the 

stomach after 2 h. Anything that reduces interfa-

cial tension, e.g. liquid paraffin and simeticone, and so breaks the foam, is incompatible with alginate-antacid preparations.

Antisecretory agents

Confirmed refluxing or oesophageal damage is an indication for adding an inhibitor of acid 

secretion.

The drugs of choice, especially for resistant cases 

and if stricture or oesophageal erosion occurs, are 

the PPIs, i.e. esomeprazole, lansoprazole, omepra-

zole, pantoprazole and rabeprazole sodium. These 

are much more potent inhibitors of gastric acid 

secretion than the H2-RAs (see below). Pantoprazole 

may have fewer side-effects than the others, but 

all are similarly effective: most experience is 

with omeprazole. Initial treatment is usually for 

4-8 weeks. Fears were originally expressed that 

prolonged suppression of acid secretion may pre-

dispose  to  malignancy,  but  experience  has 

shown that this is not a significant problem.

Patients who require long-term maintenance 

treatment  should  first  be  stabilized  on  a  PPI. 

Those with severe oesophagitis will continue to 

need full PPI doses. Patients with less serious 

disease  should  be  stepped  down  to  the  least 

expensive  regimen  that  controls  their  symp-

toms  effectively,  with  short-term  increases  for 

exacerbations.

H2-RAs, i.e. ranitidine, cimetidine, famotidine or nizatidine, are less effective than the PPIs and relieve symptoms in about 25% of patients, but higher than normal doses may be required.

Sphincter ‘strengtheners’

Metoclopramide  is  a  dopamine  antagonist  that 

increases the tone of the LOS and may be added if 

symptoms  persist.  Once  symptoms  have  been 

relieved, the regimen should be continued for at 

least 2 months, after which the dose may be care-

fully reduced, titrating the dosage against symp-

toms  for  individual  patients.  Although  not 

licensed for this indication in the UK, the anti-

emetic agent domperidone is another dopamine 

antagonist that may be helpful (in the short term, 

because it is not recommended for chronic use). 

Because of their mode of action, both of these 

antagonize the effects of anti-Parkinson drugs, 

with an increased risk of extrapyramidal symp-

toms (EPS; see Chapter 6), and of some cardiac 

stimulants,  e.g.  dopamine  and  dobutamine,  but

these are used rarely. Because domperidone does not pass the blood-brain barrier it rarely causes EPS and does not interact with levodopa centrally. There is also an increased risk of extrapyramidal effects and neurotoxicity with lithium.

Motility stimulants

Metoclopramide  and   domperidone,   referred   to above, also help by hastening gastric emptying, thus   reducing   the   amount   of   acid   gastric contents  and  so  the  possibility  and  adverse effects of refluxing.

Other drugs

Mucosal protectants (e.g. tripotassium dicitratobis-

muthate and sucralfate), have been used (unli-

censed  indications),  but  are  only  moderately 

successful. Sucralfate is most frequently used: the 

tablets are readily dispersed in water and for 

treating oesophageal reflux this mode of admin-

istration appears preferable to swallowing the 

tablets whole.

Carbenoxolone is rarely used now in the UK, because of its limited effectiveness and cortico-

steroid-like side-effects, e.g. hypertension, heart failure and hepatic and renal impairment.

Management: surgery

If symptoms persist despite an adequate trial of drugs, surgery may occasionally be indicated to repair a hernia or to refashion the cardia to mini-

mize refluxing. Severe, prolonged oesophageal irritation may result in haemorrhage, with or 

without perforation. This is an emergency situa-

tion, the management of which is discussed 

below. It is now possible to repair oesophageal perforation by laparoscopic surgery.

Dysphagia

Difficulty in swallowing food or pain on swal-

lowing   may   have   many   causes,   including motility and nerve disorders, local trauma and malignancy.  It  is  an  occasional  symptom  of diabetes mellitus, due to autonomic neuropathy (see Chapter 9), and of Crohn’s disease (p. 114). Dysphagia is always a serious symptom that 

merits urgent investigation.

Globus syndrome is an apparent dysphagia 

characterized by a ‘lump in the throat’ with no 

demonstrated  physical  cause,  and  is  usually 

experienced by anxious or depressed patients 

who can nevertheless swallow food. Once inves-

tigations have ruled out significant pathology, 

the  only  treatment  is  reassurance,  although 

extensive  investigations  may  be  needed  to 

achieve this end.

Achalasia, i.e. inability to swallow solids and 

liquids, is caused by a failure of oesophageal peri-

stalsis and/or of the LOS to open on swallowing. 

Oesophageal  manometry  will  help  to  decide 

which of these is causative. The characteristic 

symptoms are a long history of central chest 

pain, progressive dysphagia and a tendency to 

regurgitate food, especially if the patient lies 

down after a meal. Achalasia often occurs in 

young  patients,  who  sometimes  experience 

severe pain caused by ineffective oesophageal 

contractions. Treatment is usually surgical, by 

dilatation of the LOS, or occasionally more radi-

cal surgery, but reflux oesophagitis tends to recur 

after both procedures. Injections of botulinum A 

toxin, which paralyses the neuromuscular junc-

tion and so relaxes the cardia, have also been 

used successfully.

Systemic sclerosis is characterized by wide-

spread, diffuse tissue fibrosis, and is usually the 

province of the rheumatologist (see Chapter 12). 

In the oesophagus, systemic sclerosis causes a 

functional disability, with symptoms of dyspha-

gia and heartburn. Treatment is symptomatic, 

because there is no adequate specific therapy.

Oesophageal bleeding

Aetiology

Bleeding   usually   occurs   from   oesophageal 

varices,   which   are   distended   anastomoses 

between the portal and systemic circulations. 

These occur around the lower part of the oesoph-

agus (Figure 3.4) and are a consequence of portal 

hypertension, which is usually caused by restric-

tion of blood flow through the liver as a result of 

alcoholic cirrhosis (p. 155). Changes in intra-

vascular pressure and local trauma may cause 

massive haemorrhage from the varices, with a

30-50% mortality rate. Any significant haemor-

rhage  will  cause  haematemesis (vomiting  of 

blood), while less serious bleeding will cause 

melaena (tarry, black, blood-laden stools). The 

risk of bleeding is related to the severity of the 

underlying  liver  disease.  In  endemic  areas  of 

the  tropics,  schistosomiasis (bilharzia)  is  a 

common cause, because the parasites invade the 

liver and block the hepatic circulation.

Management

Bleeding varices are a medical emergency. Emer-

gency treatment is with blood transfusions or 

plasma expanders. Applying direct pressure with a special balloon catheter in the oesophagus 

usually controls bleeding.

Terlipressin  or  vasopressin  (antidiuretic  hor-

mone), which cause constriction of the splanch-

nic blood vessels and so reduce portal venous 

pressure, may be given as a temporary emer-

gency measure. However, about 50% of patients 

fail to respond, even when these are combined 

with  GTN  to  promote  portal  vein  dilatation. 

Terlipressin is the better tolerated drug and has 

a longer  half-life,  but  is  considerably  more 

expensive.

Once haemorrhage has been controlled (or 

occasionally as a first choice), elastic band liga-

tion of the bleeding veins is preferred because it 

is probably more effective and leads to fewer 

complications. Alternatively, injecting a venous 

irritant (i.e. sclerotherapy), using ethanolamine 

oleate or sodium tetradecyl sulphate or adrenaline 

(epinephrine) via an endoscope, either to oblit-

erate the vein or to constrict it, is more than 90% 

effective. Both of these treatments may need to 

be repeated until all identifiable bleeding sites 

have been treated, but bleeds may still recur.

Octreotide, a long-acting octapeptide analogue 

of  somatostatin, has also been injected intra-

venously to cause venoconstriction (presumably 

lanreotide acts similarly), but this is an unlicensed 

indication. Octreotide appears superior to somato-

statin and is safer and cheaper than terlipressin.

Very rarely, patients may require surgical inter-

vention to fashion a portosystemic shunt, which 

diverts blood away from the varices. In severe 

cirrhosis, liver transplantation may be indicated, 

but is rare.

In the longer term a negatively chronotropic 

antihypertensive, usually propranolol (see Chapter

4), may prevent recurrence.

Helicobacter infection and gastroduodenal disease

Organism and epidemiology

Helicobacter  pylori  was  first  identified  in  the 

early 1980s. It is implicated in chronic active 

gastritis,  non-ulcer  dyspepsia,  peptic  ulcer, 

gastric cancer and a rare low-grade lymphoma 

(MALT[mucosa-associated  lymphoid  tissue] 

lymphoma). It is a Gram-negative, multiflagel-

late,  spiral,  microaerophilic  bacterium,  which 

appears  to  be  an  obligate  parasite  of  gastric 

epithelium. H. pylori has been found only on 

gastric epithelium under the mucus layer and 

on areas of gastric-type epithelium that some-

times  occur  in  the  duodenum,  but  not  else-

where in the gut. It has powerful flagellae that 

help it to penetrate the mucus, and survives in 

the hostile gastric environment partly because 

of  the  bicarbonate-laden  mucus  and  partly 

by  the  action  of  bacterial  urease  to  produce 

ammonia.

Two strains are distinguished on the basis of 

cytotoxin production, a virulence factor that 

determines duodenal ulcerogenicity, i.e. cagA 

(cytotoxic antigen positive), and cagA-. Both 

strains occur in Western countries, so typing for 

this may become a routine aid to determine 

whether eradication treatment is required. In 

developing countries, most isolates are cagA , so 

typing is not helpful there.

Serology is an unreliable indicator of infection 

because of the high carrier rate of H. pylori in the 

general population: 20% of people are carriers by 

the age of 30, and 50% by the age of 60. Much 

higher carrier rates occur in patients with active 

gastritis and duodenal ulcer (about 95%) and 

with gastric ulcer (75%). These prevalence rates 

are  falling  in  the  UK,  probably  because  of 

improving hygiene. The high rate of gastric can-

cer in Peru is associated with a 50% prevalence of

H. pylori in infants from poor families, and 60% 

of children by age 10 years, whereas juvenile

infection is uncommon in the UK and the gastric cancer rate is much lower.

Investigation

H. pylori is urease-positive, i.e. it breaks down urea 

to carbon dioxide and ammonia, and this prop-

erty is used to detect its presence. The patient 

takes an oral preparation of carbon-13 urea, and 

the presence of labelled carbon dioxide in the 

breath  is  detected.  Detection  of 13C  requires 

samples to be sent to a laboratory with a mass 

spectrometer.  The  test  is  very  sensitive  and 

specific. Endoscopic biopsy samples can also be 

examined for the organism microscopically and 

by culture: these samples are rapidly checked for 

urease by incubating in a medium containing 

urea, the production of ammonia being detected 

by the colour change of an indicator (CLO test). 

Both the isotopic and CLO tests have about 95% 

specificity, but the former is less invasive. PPIs 

and bismuth inhibit the bacterial urease and so 

should be stopped for at least 2 weeks before 

urease testing. Recent antibiotic use, i.e. within

4 weeks, may also give false-negative results.

An immunoassay for Helicobacter antigen in 

stool samples is widely available and can be used 

for diagnosis and for monitoring the eradication 

process.

Infection and epigastric symptoms

Although  Helicobacter  infection has not been proven unequivocally to be the prime cause of gastritis  and  gastroduodenal  ulceration,  the circumstantial evidence is very strong:

•  Gastritis  developed  in  two  early  research 

workers   with   previously   normal   gastric

mucosa after deliberate self-infection. 

•  The  presence  of  the  organism  in 95%  of

symptomatic patients.

•  Resolution of symptoms when the organism 

is eradicated.

•  Eradication of the organism results in longer 

remissions (up to 4 years in duodenal ulcer

disease), than does simple suppression of acid production.

•  The presence of mucosal changes in asympto-that such infection may also be implicated in 

matic carriers, and association with a series of premalignant gastric changes.

•  H. pylori causes:

-  local cytokine release, e.g. IL-6 and IL-8, 

and so recruitment of inflammatory cells;

-  suppression  of  somatostatin  release  and

stimulation of histamine levels. The sum of these effects causes increased acid produc-

tion, which produces gastric metaplasia in the   duodenum,   duodenal   colonization with H. pylori, and duodenal ulcer.

There appear to be two sites of gastritis from 

Helicobacter infection: in the pyloric antrum and 

in the body of the stomach. Infection of the 

pyloric  antrum  seems  to  be  associated  with 

increased acid production and duodenal ulcer, 

but a low risk of gastric cancer. A minority of 

patients have infection of the body of the stom-

ach and this is accompanied by reduced acid 

secretion and so protection against GORD: this 

may reflect colonization by the non-pathogenic 

(cagA-, commensal) strain or a genetic predispo-

sition. Thus elimination of Helicobacter infection 

from the gastric body, which allows a variable 

recovery in gastric acid production, may be the 

cause  of  an  observed  increased  incidence  of 

GORD (see below).

Unfortunately, infection of the body of the 

stomach predisposes to gastric mucosal atrophy 

and, in some patients, to gastric cancer. This may 

possibly be caused by suppression of ascorbic 

acid secretion into the stomach or to the pro-

longed inflammation of mucosal cells, because 

ascorbic acid inactivates potentially carcinogenic 

nitroso-compounds and scavenges oxidizing free 

radicals. There is limited evidence from Japan 

that elimination of H. pylori infection reduces 

the incidence of new gastric cancers in those 

who had undergone surgery for earlier gastric 

neoplasms. Although it may be prudent to erad-

icate H. pylori in patients who need long-term 

acid suppression for peptic ulcer, and so prevent 

gastric cancer, the possibility of exacerbating 

GORD  should  be  anticipated  and  patients 

warned to report any increased frequency or 

severity of symptoms, or any new symptoms.

Because chronic infection with H. pylori causes 

increased fibrinogen levels, it has been suggested

myocardial infarction (see Chapter 4).

Pharmacotherapy

Specific  treatment  should  be  used  when  H. 

pylori is found in association with peptic ulcer, 

especially duodenal ulcer. Some clinicians treat 

prophylactically if Helicobacter is found, even in 

the  absence  of  symptoms.  However,  if  the 

preliminary  observations  reported  above  are 

substantiated, we may need to be much more 

selective  in  the  treatment  of  patients  with 

proven or suspected Helicobacter infection.

Eradication of H. pylori

This is usually achieved using triple therapy 

with a PPI plus antibiotics, or bismuth chelate 

plus antibiotics. There are six different, though 

similar,  regimens  but  none  has  been  proved 

superior. Some that have been used successfully 

(about 90% eradication) are given in Table 3.5. It 

is unclear why a PPI is included as there have 

been reports of success with antibiotics alone. 

However, it may minimize further damage to a 

pre-existing ulcer and provide superior condi-

tions for ulcer healing. Dual therapy regimens 

comprising a PPI and a single antibiotic are not 

recommended, because resistance is common.

One week of triple therapy is usually adequate, 

but 2 weeks’ treatment has eliminated the bacte-

ria in 91% of patients in one trial, with no 

relapse within a year. However, these longer reg-

imens are often associated with more side-effect 

and  compliance  problems.  Other  trials  have 

demonstrated protection against relapse in duo-

denal ulcer for up to 4 years. It is not known 

whether this represents a ‘cure’. Although re-

infection is unusual, ulcer recurrence may be 

expected if recolonization occurs.

Amoxicillin,  nitroimidazole  and  clarithromycin 

resistance has been reported, and this is trans-

missible to other bacteria. Regimens using amox-

icillin plus either clarithromycin or metronidazole 

(some clinicians use tinidazole) are suitable for 

use in the community, but those combining 

clarithromycin  or metronidazole  without amoxi-

cillin are best managed by hospital consultants with testing for resistance and eradication on 

site. Resistance testing should preferably be done before treating: this requires endoscopy with 

biopsy and laboratory culture.

Mild side-effects are common with regimens containing bismuth, metronidazole, clarithromycin and tinidazole, but side-effects causing cessation of  treatment  are  rare.  Antibiotic-associated 

colitis (AAC, see Chapter 8) is an uncommon side-effect of triple therapy.

A 3-day quadruple regimen, i.e. a PPI    bis-

muth     two antibiotics, is reported to be as 

effective as 1 week of triple therapy, with fewer 

side-effects, and a quadruple regimen is also used 

if a triple regimen fails to eradicate the organism.

These regimens are recommended for patients with proven peptic ulcer disease with H. pylori infection and where there is frequent relapse or a  history  of  complications.  They  should  be considered whenever long-term treatment with antisecretory agents is contemplated.

Eradication therapy gives a high remission rate in MALT lymphoma (see Chapter 10).

NSAID-induced ulceration and H. pylori infection

The   nature   of   the   ulcerogenic   interaction 

between H. pylori and NSAIDs is unclear. NSAID-

induced ulcers are more likely to bleed than 

those caused by H. pylori, possibly because the 

organism stimulates the production of gastro-

protective PGE2, whereas NSAIDs cause inhibi-

tion   of   PG   production (see   Chapter 12). 

However, although H. pylori eradication reduces 

the risk of new NSAID-induced ulcers in patients 

who  have  not  had  previous  ulceration,  the 

situation is less clear in those with pre-existing 

ulceration.

One study has shown that in patients with 

NSAID-induced symptomatic gastric ulcers, sup-

pression of acid production with omeprazole is 

probably adequate. However, if there is a proven 

history of peptic ulceration and H. pylori infec-

tion,  eradication  before  initiating  essential 

NSAID treatment may reduce the risk of new 

ulcers. None of this applies to patients taking 

low-dose aspirin.

A recent review has confirmed that H. pylori 

eradication is a first choice in endoscopically 

proven peptic ulcer and functional dyspepsia, 

and as one option for treating uninvestigated 

dyspepsia.

Dyspepsia

The  general  anatomy  of  the  stomach  and 

duodenum is illustrated in Figure 3.8 and the 

physiology has been outlined above.

Aetiology

A self-diagnosis of ‘indigestion’ is one of the most common reasons for patients to consult a doctor or pharmacist. It is estimated that 40% of the UK population have dyspeptic symptoms 

annually, 5% consult their doctor and one-fifth of those who do so are referred to consultants for possible endoscopy (see below).

The term ‘dyspepsia’ is used to describe upper 

abdominal discomfort, usually related to food or 

alcohol  intake.  The  symptoms  reflect  several 

different pathologies, and of those who have 

endoscopy, 40% have functional non-ulcer dys-

pepsia (NUD), 40% have GORD (see above), 13% 

have some form of ulcer and3% have gastric or 

oesophageal cancer. Symptoms in the remainder result from non-gastric causes, e.g. hepatic, pan-

creatic or cardiovascular. The term ‘functional’ indicates that function is abnormal but there is no identified lesion or cause and these are often resistant to treatment.

Mistaken ideas about digestion are very com-

mon, but there is no evidence that any particu-

lar foods are ‘indigestible’, except for insoluble 

fibrous foods, the intake of which is beneficial. 

True dyspepsia, i.e. failure of digestion due to 

inadequate acid and pepsin production, is rare, 

and the possible causes of symptoms are listed in 

Table 3.6.

Clearly the range of possible pathologies is 

large, so careful history taking, examination and investigation are necessary to exclude potential-

ly serious disease. Only some of these diseases are dealt with here and the appropriate sections should be consulted.

Investigation and diagnosis

The characteristics of individual symptoms, or 

combinations of symptoms, have poor discrimi-

natory ability and are an unreliable guide to 

their origin. An approach to investigation and 

management is shown on p. 101. However, over-

enthusiastic  medication  or  investigation  may 

perpetuate false ideas of organic disease.

Medication review should be used to guide the 

elimination of the many agents likely to cause gastric discomfort. Only one medicine at a time 

should be eliminated, or replaced if the treat-

ment is essential, giving each change 1 month 

before concluding whether the medicine is pos-

sibly implicated. If the symptoms do not remit, 

that  medication  is  clearly  not  implicated. 

However, if the symptoms do remit, the only 

way to be confident that that product was caus-

ing the dyspeptic symptoms is to rechallenge, 

i.e. reintroduce it and see whether the symptoms 

recur. Further, it is necessary to consider whether 

more than one product, or a combination of 

products, is causing the problem, because so 

many are likely to cause epigastric disturbance.

Mild symptoms in patients under 55 years of age do not need initial investigation unless there are associated alarm symptoms, i.e.

•  dysphagia (pain or difficulty in swallowing); 

•  unexplained microcytic hypochromic anaemia

(see Chapter 11), anorexia or weight loss; •  persistent vomiting;

•  haematemesis and/or melaena; 

•  recent onset of progressive symptoms.

Although routine endoscopy is not recom-

mended in the investigation of dyspepsia unless 

alarm  symptoms  are  present,  new  dyspeptic 

symptoms in older patients raise the possibility 

of gastric or oesophageal cancer, and so a need 

for gastroscopy.

Patients who have not been endoscoped are 

classed  as  having  uninvestigated  dyspepsia. 

Endoscopy enables a distinction to be made 

between GORD, endoscopically negative reflux 

disease, NUD, peptic ulcer disease (see below) 

and  cancer  or  precancerous  states.  Barret’s 

oesophagus describes islands of columnar cells 

in the normal squamous cells, and is a precursor 

to adenocarcinoma (see Chapter 10). By the time 

cancer is diagnosed it is usually inoperable.

NICE  has  issued  guidelines  for  specialist referral:

•  Immediate  (same   day)  -   dyspepsia   with

significant   gastrointestinal   bleeding,   e.g.

vomiting large amounts of blood.

•  Urgent (within 2 weeks) - patients of any age 

with dyspepsia and any of the following:

-  chronic   gastrointestinal   bleeding,   e.g. 

vomiting small amounts of blood, blood in 

stools;

-  progressive dysphagia;

-  progressive unintentional weight loss;

-  persistent vomiting;

-  iron deficiency anaemia;

-  epigastric mass;

-  suspicious barium meal result.

•  Urgent (within 2 weeks) - patients aged 55 or 

over if dyspepsia symptoms are:

-  recent in onset and unexplained, e.g. by 

NSAID consumption;

-  persistent, i.e. continuing for more than 

4-6 weeks, dependent on severity.

Pharmacotherapy

Lifestyle advice (e.g. diet, smoking, drinking and weight reduction if overweight) should be given, but it is often difficult for patients to change 

longstanding habits.

NICE has issued guidelines on the manage-

ment of simple (uninvestigated) dyspepsia (see References and further reading, p. 162).

Antacids

Self-medication with antacids is widespread and may be acceptable in patients under 40 years of age, provided that symptoms are not too severe and do not recur frequently.

The occurrence of drug-induced gastritis indi-

cates a need to review whether this treatment 

should be continued. If it is essential, then an 

alternative formulation that is less irritant may be  available.  Alternatively,  the  concurrent 

administration of a PPI, H2RA, PG or sucralfate is probably appropriate.

Antacids are available in a large variety of 

preparations (Table 3.7). Soluble antacids (i.e. 

simple sodium, calcium and magnesium salts), 

are unsuitable for anything other than short-

term use, because they may cause bowel upsets, 

aggravate fluid retention and heart failure, or 

produce  metabolic  disturbance.  Patients  who 

drink a lot of milk to obtain relief and take calci-

um concurrently are particularly liable to devel-

op hypercalcaemia (the ‘milk-alkali syndrome’). 

However,  some  patients  like  to  take  sodium 

bicarbonate, which aids eructation of wind and 

may provide relief, but this should not be taken 

regularly and is contra-indicated in those on a 

salt-restricted diet and in heart failure. The types of antacids in use are summarized in Table 3.7 and their side-effects in Table 3.8.

The most desirable types of antacids are mix-

tures or complexes of aluminium and magne-

sium.  Aluminium  compounds  alone  tend  to 

cause constipation, and magnesium alone can 

cause diarrhoea. Combinations of the two in 

appropriate proportions tend not to upset bowel 

habits.  Suspensions  are  more  effective  than 

tablets, but less convenient for patients with fre-

quent  symptoms.  For  unknown  reasons,  the 

pain relief is unrelated to neutralizing capacity, 

relief being obtained with doses (e.g. 10-20 mL 

of a commonly used suspension such as co-

magaldrox), that do not markedly raise gastric 

pH. Antacids may have some mucosal protective 

effect by forming a coating on damaged tissue, 

and some may adsorb acid as well as neutralizing 

it. It is reasonable to start with a product of low 

to moderate neutralizing capacity and to change 

to one of higher capacity (Table 3.9) if relief is 

inadequate. However, patient preference is the 

best guide to antacid selection. Antacids should 

be taken regularly to be effective.

Very high doses of antacids (about 200 mL per 

day) are required to neutralize acid effectively: 

this abolishes peptic activity and assists ulcer 

healing. However, these high doses are usually

unacceptable  to  patients,  especially  as  they 

obtain  satisfactory  symptomatic  relief  with 

much lower doses. Further, the prolonged use of 

high doses of insoluble antacids is particularly 

likely to produce adverse reactions. If gastric acid 

is a problem, an antisecretory agent is preferable 

(see below).

The basal (unstimulated) gastric acid output is 

about 3 mEq/h, and this is increased by about

30 mEq per main meal, plus smaller amounts 

for snacks. Accordingly, it has been suggested 

that doses sufficient to neutralize 200 mEq of 

hydrochloric acid per day are effective in most 

patients.  Further,  buffering  capacity  is  impor-

tant, and that of some OTC products may be 

too high, though the relevance of this is not 

clear.

There is little evidence to suggest that products containing  simeticone  are  of  special  benefit unless wind is a problem or patients find such products particularly useful. Equally, there does not appear to be a role for products containing alginates unless there is proven reflux oesophagi-

tis. Despite this, these relatively expensive prod-

ucts  are  frequently  prescribed  routinely  as 

antacids.  These  latter  two  classes  of  product should not be used together because they are 

physicochemically incompatible.

Antisecretory agents

Proton pump inhibitors (PPIs) should be used at full dosage for 1 month, because these are 

more effective than an H2RA or antacids. There is no evidence of which of these is preferred, so choice usually falls on the cheapest product, 

usually generic omeprazole.

If this fails to produce adequate benefit, the 

patient should be tested for H. pylori  and, if 

positive, this should be eradicated (Table 3.5). 

Although some consultants have advocated test-

ing for H. pylori as the first choice, it is probably 

not cost-effective, because of the low yield in 

younger patients and because many patients are infected  without  it  being  the  cause  of  the 

symptoms.

Failure to respond to these measures should 

prompt  a 1-month  trial  of  an  H2RA,  e.g. 

famotidine, nizatidine or ranitidine, to reduce acid 

production, or a prokinetic agent, i.e. metoclo-

pramide or domperidone, to hasten gastric empty-

ing.  The  H2RA  cimetidine  is  also  used,  but  it 

inhibits cytochrome P450 hepatic oxidation and 

so interferes with the clearance of many drugs, 

enhancing their activity. Because the H2RAs are 

less effective than the PPIs, their use has declined.

It  should  be  remembered  that  all  of  these agents  may  cause  gastrointestinal  disturbance, so  exacerbation  of  dyspepsia  or  apparent 

relapse after improvement may be due to the 

antidyspeptic product.

Figure 3.10 summarizes the factors influencing the release of gastric acid and the sites of action of antisecretory drugs and antacids.

Peptic ulcer disease

Definition

A peptic ulcer is an abnormal area of mucosa 

that  has  been  damaged  by  the  pepsin  and 

hydrochloric acid of gastric juice, with conse-

quent  inflammation  of  the  underlying  and 

surrounding tissue. Erosion may subsequently occur into the lamina propria and submucosa to cause bleeding (see Figure 3.2).

 Most peptic ulcers occur either in the duode-

num or in the stomach, where the pH is suffi-

ciently low for peptic action, although ulcers 

may also occur in the lower oesophagus, as a 

result of refluxing of gastric contents, and rarely in certain areas of the small intestine. Colonic ulcers are not included in this category.

Epidemiology

Dyspepsia (p. 91) is frequently thought of by 

patients (erroneously), as being caused by ulcer-

ation, but it usually denotes benign and tran-

sient inflammation. Nevertheless, peptic ulcers 

are common: it has been estimated that up to 

10% of the population has an ulcer at some time, 

though many of these are asymptomatic, the 

annual incidence of symptomatic peptic ulcer 

being about 0.3%.

Duodenal ulcers are four times as common as 

gastric ulcers and occur mainly in the duodenal 

cap (the first part of the duodenum, Figure 3.8); 

among  duodenal  ulcers,  half  occur  on  the 

anterior wall.

Gastric ulcers occur mostly on the lesser cur-

vature of the stomach, often near the angular 

incisure. These are usually benign, whereas an 

appreciable minority (5%) of tumours in the 

fundus and body of the stomach and the pyloric 

antrum are malignant. Most gastric carcinomas 

occur in the pyloric antrum, but it is rare for 

these to spread to the duodenum or for duodenal 

ulcers to be malignant. Gastric malignancy is much more common in Japan, Chile, Finland 

and Iceland than in the UK, the difference prob-

ably being a result of environmental factors, 

especially diet. Fortunately, the incidence of gas-

tric carcinoma is declining fairly rapidly in the 

West, but it remains the third most common 

cause of death from malignancy in the UK and 

has a poor prognosis (10% survival at 5 years).

Aetiology

The aetiology of peptic ulcer disease is multifac-

torial, the mechanisms normally operating to 

protect the mucosa from self-digestion by the 

acid and pepsin of gastric juice either failing or 

being overcome by a combination of injurious 

factors (Figure 3.9). The most common causes of 

peptic ulcer in the UK are H. pylori infection and 

NSAID ingestion. The old hypothesis that ulcer-

ation is caused simply by hyperacidity is not

tenable, because about 70% of gastric ulcers and 50% of duodenal ulcers (i.e. about 55% of all ulcers) are not associated with abnormally high acid production. However, gastric ulcers occur-

ring near the pylorus may be associated with 

combined H. pylori infection plus hyperacidity, as are many duodenal ulcers.

Heredity is also important: the development of 

duodenal ulcer at an early age tends to run in 

families. Ulcers are also more common in blood 

group  O  subjects  and  in  those  who  do  not 

secrete  blood  group  antibodies  into  gastric 

secretions, but the reasons for this are obscure.

Added to these naturally-occurring factors are 

a number of social and environmental ones, the 

most important being smoking. The ingestion of 

some drugs, especially NSAIDs and alcohol, also 

promotes acute ulceration. Spicy foods do not 

cause ulceration, but may aggravate symptoms.

‘Stress ulcers’ occur in seriously ill patients, 

and are common in patients in intensive care units. Whether sustained emotional stress leads to  chronic  ulceration  is  unclear,  although  it undoubtedly triggers gastrointestinal discomfort and may aggravate symptoms. Hyperacidicity, dyspepsia,  and  occasionally  ulceration,  are 

common psychosomatic features of psychiatric illness (see Chapter 6).

Balance between protective and erosive factors

Much  more  attention  is  now  focused  on  the 

factors  responsible  for  the  maintenance  of 

mucosal integrity. These include the secretion 

of  bicarbonate-laden  mucus  and  the  turnover 

of  mucosal  cells  every 36-48 h,  factors  that 

depend  on  an  adequate  blood  supply.  These 

are  opposed  by  several  factors  that  either 

promote erosion or facilitate it, including bile 

reflux,  chronic  gastritis (from  gastric  stasis, 

diet  or  alcohol),  local  ischaemia  and  hyper-

acidity (40%).  This  balance  is  illustrated  in 

Figure 3.9.

The damage caused to the mucosa by reflux 

of bile through an incompetent pyloric sphinc-

ter (Figure 3.11) possibly accounts for the high 

incidence of ulcers in the pyloric antrum. The 

role of H. pylori has been discussed above, but 

there has also been considerable interest in the 

role  of  PGs  and  their  synthesizing  enzymes 

(cyclo-oxygenases; see Chapter 12), and small 

doses of PGs have been shown to inhibit acid 

secretion, promote the repair of damaged gastric

 mucosa, and to stimulate gastric blood flow in 

animal  studies.  PGs  have  therefore  been 

described  as ‘cytoprotective  agents’,  though 

there is considerable debate as to whether this 

description  is  justified.  This  partly  explains 

why  NSAIDs,  which  inhibit  PG  synthesis,  are 

ulcerogenic.

Clinical features

Pain  is  the  outstanding  feature,  varying  from 

‘discomfort’ to ‘severe’. It is usually felt in the 

epigastric  region (Figure 3.1(c)),  although  in 

longstanding,  severe  cases  in  which  the  ulcer 

penetrates into other organs, the patient may 

complain of backache or lower abdominal pain. 

The  pain  is  often  described  as ‘burning’  or 

‘gnawing’. Sometimes a patient points with one 

finger  to  a  spot  in  the  epigastric  region (the 

‘pointing sign’), and this tends to indicate an 

ulcer  rather  than  simple  gastritis.  The  occur-

rence  of  pain  in  either  the  left  or  right 

hypochondrium  is  an  unreliable  guide  to  the 

site of ulceration.

Spontaneous  night  pain,  which  may  be 

relieved by milk or antacid ingestion, may wake 

the patient regularly at about 2 a.m. and tends to 

be more common with duodenal ulcer, although 

it is not known why. Generally foods - or partic-

ular items of food - do not cause pain, but strong coffee or tea should be taken in moderation. 

Although  it  has  been  said  that  gastric  ulcer patients may complain of pain about 2 h after eating, whereas those with duodenal ulcer may find that food or milk relieves pain, this varies considerably between patients.

The pain may sometimes be ascribed to angi-

na  or  myocardial  infarction (see  Chapter 4), 

but the pain from these tends to be constrict-

ing/crushing in character. Further, none of these 

symptoms or signs is diagnostic, and gastric and 

duodenal  ulcers  cannot  be  differentiated  on 

clinical grounds. All peptic ulcers tend to give 

periodic  symptoms,  the  recurrence  having  no 

obvious cause, and the symptom-free intervals 

decrease with time in the absence of effective 

treatment. The most significant features are:

•  waking from sleep with epigastric pain; •  periodicity of symptoms;

•  a family history of peptic ulcer.

Investigation and diagnosis

History

The discriminatory value of a history alone is 

poor, because it has been shown that symptoms 

such as postprandial pain and nausea occur with 

similar  frequency (in  about 40%  of  patients) 

in NUD, peptic ulcer disease, irritable bowel 

syndrome (IBS), gallbladder disease and gastric 

carcinoma,   although   episodic   pain   is   very 

uncommon with the last two of these condi-

tions.  However,  history  taking  must  not  be 

omitted (see Table 3.3), not least because the 

information is obtained quickly and easily.

Patients  requiring  special  investigation  are 

those  with  complications (e.g.  haematemesis, 

gastrointestinal  haemorrhage  or  suspected 

pyloric stenosis), those who fail to respond to 

treatment,  and  patients  taking  NSAIDs  whose 

symptoms fail to remit when the drug is stopped.

Investigation

The principal concern when a patient presents 

with symptoms suggestive of peptic ulcer is not 

to miss gastric cancer, but we have noted that 

the predictive value of the history is poor. The 

most significant factor for cancer is age, and any 

patient aged over 45 years with new persistent 

dyspeptic symptoms that have no obvious cause, 

should   be   investigated   urgently.   Additional 

indicators of possible malignancy are:

•  male sex; 

•  smoking;

•  a family history of gastric cancer; •  severe pain;

•  dysphagia, especially with vomiting; •  unexplained weight loss;

•  microcytic, hypochromic anaemia (i.e. iron 

deficiency anaemia due to chronic bleeding),

also  causing  melaena  (black,  tarry  faeces 

caused by the presence of partially digested 

blood);

•  epigastric  mass  detected  by  palpation  or 

ultrasound;

•  progressive symptoms.

In the UK, the average delay from the onset of 

symptoms to surgery for gastric cancer is about 7 

months. This is far too long, because studies in 

Japan, where the disease is more common, have 

shown  that  early  diagnosis  and  treatment 

improves the prospects enormously. In Japan, 

the average overall 5-year survival rate is about 

90%, whereas it averages about 10% in the UK.

Fibre-optic endoscopy is the most accurate 

investigation for the diagnosis of peptic ulcer 

and gastric cancer, and also permits biopsies and 

brush cytology (the removal of superficial cells 

for examination). If this technique is not readily 

available, or is contra-indicated in a particular 

patient because of the possibility of oesophageal 

or gastric perforation, a barium meal radiograph 

(Figure 3.12) gives good results. However, up to 

20% of duodenal ulcers may be missed with this 

technique, especially if they are below the duo-

denal cap. The diagnostic yield from gastroscopy 

in most Western countries is poor and routine 

gastroscopy is not done, so early diagnosis is 

unusual, unlike in Japan, where they screen with 

mobile X-ray units.

Gastric secretion tests are of limited value and are now used only in special circumstances.

Complications

One of the most common of these is bleeding, 

which may vary from minor chronic blood loss 

that would eventually cause anaemia, to moder-

ate bleeding causing melaena or haematemesis. 

The stomach is rather intolerant of blood: if the 

amount  is  small  and  the  bleeding  point  is 

inactive, the blood may be partly digested and 

appear brownish in vomit, resembling coffee 

grounds. If bleeding is active and significant, 

then fresh blood will be vomited, and this is an 

alarming symptom.

A haemorrhage, from the invasion of the arte-

rial bed underlying an ulcer, may occasionally be life-threatening. Therapeutic endoscopy, using rubber band ligation, laser coagulation, electro-

coagulation, injection with adrenaline (epineph-

rine) or sclerotherapy, significantly reduces the need for emergency surgery.

Unobstructed perforation into the abdomen 

may occur and this is an emergency requiring surgery and broad-spectrum antibiotics. Pene-

tration  into  adjacent  organs (e.g.  liver  or 

pancreas), produces severe continuous pain, and pancreatitis may ensue.

Recurrent damage may result in scarring and 

the consequent contraction may cause gastric or 

duodenal stricture and obstruction. This tends to 

be  more  common  with  duodenal  ulcer.  The 

symptoms of this are a feeling of fullness after 

modest meals, nausea and vomiting. A barium 

meal  may  show  an  ‘hour-glass’  stomach,  or 

food trapping and gastric distension. Surgery is 

usually required.

If gastric carcinoma occurs it is usually present 

at the outset, but a benign chronic ulcer may 

undergo malignant change, although this is rare.

Management

The objectives of management are to:

•  relieve pain and discomfort; •  accelerate healing;

•  prevent recurrence and complications.

are usually based on patient age. 

Malignancy is rare below 45 years of age, so ini-

tially these patients may be treated conserva-

tively. This may miss up to 3% of gastric cancers 

but gives a reasonable compromise between risk 

and workload. Those patients aged under 45 

with neoplasms should be identified fairly quick-

ly by their lack of response to treatment and/or 

early relapse.

General measures

Regular small meals are advisable, and alcohol, 

strong coffee or tea should be taken only in 

moderation, because they are strong stimulants 

of acid secretion. Late snacks are best avoided, 

because they stimulate nocturnal gastric secre-

tion. Apart from this, there is no evidence that 

any special diet is beneficial, although it seems 

likely that some dietary factor is likely to be 

implicated  in  causation,  but  this  may  differ 

between patients. Clearly, patients will avoid any 

foods that they believe provoke or aggravate 

their symptoms. Rigorous dietary restriction is 

stressful for the patient and may be counterpro-

ductive, but smoking and alcohol, which are 

known risk factors, should be strongly discour-

aged  and  patients  should  be  warned  against 

taking any medication, especially aspirin  and 

NSAIDs, which is liable to cause gastrointestinal 

distress.

Anxiety and stress should be reduced if possi-

ble, by the adoption of a more tranquil lifestyle 

and the cultivation of hobbies, but this is diffi-

cult to achieve. Bedrest may be a useful adjunct 

in the short-term relief of severe symptoms, but 

has no advantage over modern drug treatment.

Pharmacotherapy

Aims

The aims of pharmacotherapy are to:

•  relieve  symptoms,  by  neutralizing  acid  or 

reducing acid secretion;

•  promote healing, by enhancing mucosal resis-

tance, eliminating bacterial gastric infection

and reducing acid secretion.

Ulcers  are  intrinsically  self-healing  if  the 

imbalance between erosive and protective fac-

tors can be corrected. Healed ulcers are often 

found at postmortem examination in individu-

als with no prior ulcer history. With the excep-

tion  of  sucralfate  and  bismuth  chelate, ‘ulcer-

healing’ drugs do not actually heal or stimulate 

repair, but correct the imbalance and so promote 

natural healing. About one-third of ulcers remit 

spontaneously.

Antacids

These are indicated as sole therapy in young 

patients (under 40   years)   and   those   with chronic, stable, mild symptoms.

Antisecretory agents

These include the PPIs and H2RAs (Figure 3.9).

Proton pump inhibitors.   Omeprazole, panto-

prazole and the more recent agents esomeprazole, 

lansoprazole and rabeprazole, powerfully inhibit 

H /K -ATPase, the final common pathway for 

hydrogen  ion (proton)  secretion (hence  the 

‘proton pump’), that is present uniquely in pari-

etal cells. They are more effective antisecretory 

agents than the H2RAs, and are usually the drugs 

of first choice.

They are enteric-coated prodrugs that are acti-

vated in the liver and bind irreversibly to the 

extracellular (luminal) domain of the transmem-

brane H /K -ATPase in the gastric pits, to pro-

duce almost complete achlorhydria following a 

single  dose.  Omeprazole  was  the  first  of  this 

group, and has a plasma half-life of only 1 h, but 

because it produces irreversible enzyme inhibi-

tion its duration of action is at least 24 h. A 

single daily dose gives a peak effect after about 5 

days of continuous dosing. After a single dose, or 

when treatment has ceased, inhibition of acid 

secretion persists until new enzyme synthesis 

occurs.  The  other  agents  are  used  similarly. 

Esomeprazole is more effective than omeprazole, 

but all of the PPIs appear to be similarly effective 

at comparable dosage.

PPIs produce more rapid healing of duodenal ulcers than H2RAs, but healing rates with gastric ulcers, and the relapse rates following cessation of treatment, appear to be similar.

Side-effects and interactions.   The list of common 

side-effects is rather long (diarrhoea or constipa- tion, headache, rashes, pruritus and dizziness, 

nausea  and  vomiting,  abdominal  discomfort, 

bronchospasm, muscle and joint pain, depres-

sion, blurred vision and dry mouth), but these 

are usually mild and well-tolerated and rarely 

cause cessation of treatment. Although hepatic 

dysfunction occurs only rarely, it is prudent to 

monitor liver function before and during treat-

ment, especially if prolonged treatment is likely.

In elderly males, lansoprazole and omeprazole 

may  rarely  cause  gynaecomastia,  i.e.  breast 

enlargement. This needs careful investigation to 

exclude  serious  underlying  pathology,  e.g. 

bronchial carcinoma and testicular tumours. If 

obtrusive, mastectomy may be required, but this 

is rare.

Fears  about  possible  carcinogenesis,  which 

delayed licensing, are no longer believed to be 

significant. Omeprazole has been used for several 

years in some patients without untoward effects. 

However,  it  somewhat  inhibits  the  hepatic 

microsomal metabolism of some drugs, increas-

ing plasma levels, whereas lansoprazole is only a 

mild inducer. Caution is required with PPIs if 

patients have liver disease, are pregnant, or are 

breastfeeding.

Use  of  PPIs.   Symptomatic  H.  pylori-positive 

patients should have eradication therapy (Table

3.5), all but one of which use a PPI. In H. pylori-

negative patients, most PPIs give effective short-

term  treatment  of  peptic  and  gastric  ulcer. 

However, esomeprazole is used only for GORD, 

NSAID-associated   gastric   ulcer   and   for   the 

prophylaxis  of  gastroduodenal  ulceration  in 

those who need to continue NSAID treatment.

Generally, duodenal ulcers heal in 4 weeks and 

gastric ulcers in 8 weeks, but rabeprazole takes 

rather  longer (6  and 12 weeks,  respectively). 

GORD requires higher doses and longer treat-

ment,  e.g. 4-8 weeks’  initial  treatment  and 

possibly indefinite maintenance treatment at a 

lower dose.

H2-RAs.   These  act  by  blocking  histamine-

mediated acid secretion via the H2  receptors of 

parietal cells, and have gained wide acceptance 

as effective, safe drugs, having initially revolu-

tionized the treatment of peptic ulcer before the 

introduction of PPIs. There are now four drugs of

this class available in the UK: ranitidine, cimeti-

dine, famotidine and nizatidine. The first two of 

these have gained widespread acceptance, but all 

seem  to  be  similarly  effective  at  therapeutic 

dosage and are well tolerated. Famotidine, nizati-

dine and ranitidine do not appear to share the 

adverse hormonal reactions and interactions of 

cimetidine.

Dosing   in   acute   attacks.   H.   pylori-negative 

patients   normally   use   a   dosage   regimen 

consisting of a single night-time or twice-daily 

dose, though gastric ulcers may need larger doses 

and more prolonged treatment than duodenal 

ulcers. There is some evidence that dosing after 

the  evening  meal  gives  superior  results  to 

bedtime dosage. These doses provide healing in 

about 70% of gastric ulcer patients after 1 month 

and in about 80% after a further 2-4 weeks, but 

treatment may need to be extended to 12 weeks. 

Results for duodenal ulcer are somewhat better, 

and healing occurs in about 80% and 90% after

4 and 8 weeks, respectively. If patients are H. 

pylori-positive, then eradication therapy (Table

3.5) should be used.

Failure of therapy must always be investigated, 

to  ensure  that  malignant  change  has  not 

occurred and to exclude the unlikely possibility 

of  Zollinger-Ellison  syndrome (see  below). 

Antacids may be needed additionally to obtain 

rapid symptomatic relief at the start of H2RA 

therapy.

Side-effects and interactions.   There are gastroin-

testinal side-effects, and occasional CNS con-

fusion also occurs, especially in the elderly. Very 

ill and older patients are also liable to suffer the 

rarer  side-effects  of  acute  pancreatitis,  brady-

cardia or AV block (see Chapter 4), depression 

and hallucinations. The doses of all of these 

drugs may need to be reduced in renal and 

hepatic impairment.

Cimetidine,  uniquely  among  the  H2-RAs, 

potentiates the actions of warfarin, theophylline, 

phenytoin, beta-blockers and many other drugs, 

by inhibiting cytochrome P450-mediated liver 

metabolism. It should be avoided in patients 

taking these agents. Cimetidine  also has anti-

androgenic  properties  and  may  occasionally 

cause gynaecomastia and loss of libido.

However, these drugs have proved very safe 

and ranitidine, cimetidine and famotidine etc. are 

licensed  for  short-term  OTC  use  in  the  UK. 

Although it may be reasonable to use these drugs 

to treat undiagnosed dyspepsia in patients under 

about 40 years of age, patients should always be 

investigated if there are prolonged (÷14 days), 

severe symptoms, or associated systemic distur-

bance. A definitive diagnosis must always be 

made in older patients, to exclude the possibility 

of gastric malignancy.

Other  indications.   Ranitidine,  cimetidine  and famotidine, but not ranitidine bismuth citrate, are licensed in the UK for the treatment of patients with Zollinger-Ellison syndrome, a rare, slow-

growing,  gastrin-secreting  pancreatic  tumour that causes massive hypersecretion of acid and multiple   large   duodenal   and   ileal   ulcers. However, a PPI is preferred for this condition. H2-

RAs are also used to reduce gastric acid secretion, and so acid aspiration into the lungs, during 

surgical and obstetric procedures.

H2-RAs are also used for the prophylaxis of 

stress ulcers in intensive care units. However, 

patients  with  nasogastric  tubes  may  develop 

pneumonia, so sucralfate is often preferred, pro-

vided  that  the  patient  does  not  have  renal 

impairment and is not being fed enterally.

Cimetidine is used to reduce the breakdown of  pancreatic  enzyme  supplements  in  cystic fibrosis patients and in those with short bowel syndrome after extensive bowel surgery.

Mucosal protectants

These include:

•  ranitidine bismuth citrate (ranitidine bismutrex), 

a bismuth/H2RA compound;

•  tripotassium   dicitratobismuthate,   a   bismuth 

complex;

•  sucralfate, a sucrose-aluminium complex; 

•  misoprostol, a synthetic analogue of PGE1.

Apart from misoprostol, these form a protective 

sludge that binds to the ulcer crater, protecting it 

against further acid and pepsin attack. They are 

currently  of  great  interest,  because  there  is 

evidence that remissions are longer with these 

than with H2RAs.

Bismuth   chelate(tripotassium   dicitratobis-

muthate) is probably the preferred agent, because 

it has also been shown to be active against H. 

pylori, to increase mucosal PG levels, and to 

reduce pepsin secretion. If H. pylori is eradicated, 

the relapse rate is reduced to about one-third of 

that  which  occurs  if  the  organism  persists 

(80%/year).

Patients should be warned that the tablets 

cause blackening of the stools (and, occasionally, 

of the tongue), due to bismuth compound break-

down. The tablets should be swallowed with a 

glass of water (not milk), on an empty stomach: 

food, milk and antacids interfere with the coat-

ing of the ulcer by the drug, so none of these 

should be taken within 30 min of taking a dose. 

Bismuth chelate is not currently recommended 

for continuous maintenance therapy, as bismuth 

absorption and toxicity may conceivably occur. 

Although  reversible  bismuth  encephalopathy 

has been reported in patients taking normal 

doses of bismuth salts, notably in Australia and 

France,  this  side-effect  has  not  been  reported 

with bismuth chelate. The current UK licence for 

bismuth chelate allows for a 28-day dosing peri-

od, repeated if necessary. If symptoms persist, 

there  should  be  a  gap  of  1  month  before  a 

further repeat.

Other  bismuth  salts,  e.g.  carbonate,  phos-

phate,  salicylate  and  subnitrate,  have  been 

widely used as antacids and are used in some 

OTC products, but chronic use should be dis-

couraged  because of possible bismuth absorp-

tion, and patients referred to their doctor for 

investigation.

Sucralfate is also physicochemically protective and may additionally stimulate PG synthesis and the secretion of mucus. It is also used in intensive care (see above).

Although many patients take these products 

four times daily, there is evidence that twice-daily 

dosing is equally effective, and aids compliance.

Liquorice derivatives also have some mucosal-

protecting properties and were popular before 

the advent of the H2RAs. However, they are not 

now used for ulcer treatment in the UK, because 

they have mineralocorticoid properties and cause 

electrolyte  imbalances,  water  retention  and 

hypertension. Deglycyrrhinized liquorice prod-

ucts are of doubtful efficacy, but make useful 

placebos.

Other drugs

Antimuscarinics(antispasmodics,  sometimes 

referred to less accurately as anticholinergics), 

which  block  the  acid  secretion  produced  by 

vagal activity, have a long history, originating 

from galenicals derived from belladonna and 

hyoscyamus. They still have a limited use today, 

but  these  and  similar  drugs (Table 3.10)  are 

restricted in their use because they have a low 

therapeutic   index   and   cause   frequent   and 

significant antimuscarinic side-effects. They may 

occasionally be useful at night, when their side-

effects  are  less  obtrusive,  to  reduce  gastric 

motility and so retain antacids in the stomach. 

However, they are used primarily as adjuncts to 

antacids in the treatment of NUD if spasm is 

possibly implicated. Because spasm is rarely, if 

ever, confirmed objectively, this application is 

questionable.

Pirenzepine binds selectively to gastric M2-mus-

carinic receptors to reduce the secretion of both 

acid and pepsin. It has no advantages over the 

H2-RAs and has been discontinued in the UK.

Prostaglandins.   Animal   experiments   have 

indicated that PGs of the E series (PGE) have acid-inhibiting  and  cytoprotective  properties. 

Among   various   PGE   analogues,   misoprostol, 

arbaprostil and enprostil have been tested fairly 

extensively, but to date only misoprostol has been 

marketed in the UK. The last two of these have 

been shown to inhibit both gastric secretion and 

gastrin release, whereas misoprostol only inhibits 

secretion. However, the PGs appear to be less 

effective healing agents than the H2-RAs and 

provide less pain relief. The PGs also cause diar-

rhoea and abdominal pain, side-effects that may 

be severe enough to require withdrawal.

The clinical value of PGs remains to be assessed, though this is clearly an important research area. Their  use  is  contra-indicated  in  pregnancy, because they increase uterine tone.

Misoprostol  reduces  ulceration  caused  by 

NSAIDs, but does not abolish it. It is probably 

more effective than H2-RAs for the prophylaxis 

of NSAID-induced gastric ulcer, but has a similar 

activity against NSAID-induced duodenal ulcer. 

Misoprostol is marketed in the UK in combina-

tion with diclofenac and naproxen, to minimize 

the risk of ulceration from the NSAIDs. Its most 

appropriate  use  is  in  elderly  and  very  frail 

patients  in  whom  continued  NSAID  use  is 

regarded as essential, though NSAID use in this 

age group is undesirable. However, it is probably 

less effective than an antisecretory agent once 

ulceration has occurred.

Eradication of H. pylori is dealt with on p. 89. 

If NSAID treatment continues to be required, 

NSAID-associated ulcers are best managed with continuous antisecretory treatment as long as 

this treatment continues.

Drug selection and maintenance therapy

Uncomplicated disease

The correct approach to maintenance in peptic ulcer  uncomplicated  by  H.  pylori  infection  or bleeding  is  controversial,  because  relapse  is common.  The  question  is  whether  to  stop 

when  remission  occurs,  or  to  continue  with prophylactic medication.

In  younger  patients  who  have  infrequent recurrences (up  to  two  per  year),  the  usual approach is to use a PPI and discontinue this 

after 6-8 weeks and give further short courses when symptoms recur.

 If  relapse  is  more  frequent,  or  attacks  are 

severe, the patient should be investigated for 

gastric cancer. However, if this is not confirmed, 

low-dose PPI maintenance prophylaxis may be 

continued  for  long  periods,  though  some 

patients may need to continue with full doses. 

Maintenance prophylaxis is also indicated in 

debilitated or elderly patients who are unfit for 

surgery.

It  has  been  suggested  that  the  prolonged 

hypochlorhydria produced by maintenance anti-

secretory therapy may be undesirable, because 

the raised gastric pH reduces gastric digestion, 

and bacterial overgrowth, possibly resulting in 

nitrite-induced cancer (although there is no evi-

dence for this). Nitrate in preserved meats may 

cause tumours.

Complicated peptic ulcer disease

Peptic ulcer accompanied by H. pylori infection 

or haemorrhage usually responds to one of the

H. pylori eradication regimens listed in Table 3.5. 

If symptoms recur, despite confirmed eradica-

tion, retesting for H. pylori is indicated and a 

further eradication course prescribed if neces-

sary, possibly quadruple therapy (Table 3.5). The 

re-infection rate is low (1-2% in Western adults). 

Uncomplicated peptic ulcer disease responds to 

PPI medication.

It is important to realize that some peptic ulcer 

patients  may  develop  refluxing (p. 82)  after 

eradication and the GORD symptoms may be 

misinterpreted as a recurrence of peptic ulcer 

disease.

Symptoms that do not respond to these mea-

sures require investigation by gastroscopy and 

biopsy. Perforation of the ulcer into other viscera 

or  the  peritoneal  cavity  requires  emergency 

surgery.

A flow chart for the management of dyspepsia and peptic ulcer is given in Figure 3.13.

Surgery

Surgery is much less common now that effective medical management is available, but must be considered if:

•  patients fail to respond adequately to drugs; 

•  malignancy is confirmed: all non-responding gastric ulcer patients should be reinvestigated to confirm complete healing and the absence of neoplastic change;

•  relapse and rebleeding occur frequently; 

•  complications occur, e.g. bleeding or perfora-

tion.

The most common procedure is highly selec-

tive vagotomy (HSV), which is less invasive than 

partial or sub-total gastrectomy, but rarely used 

now because modern medical management is 

very effective. HSV involves cutting selectively 

only those branches of the vagus nerve that sup-

ply the gastric body and fundus where acid secre-

tion occurs (Figure 3.8), so preserving motility in 

the antrum. Clearly, however, stricture or malig-

nancy may dictate the removal of a variable mass 

of the stomach and the duodenum. HSV is a safe 

procedure with relatively few complications, but 

it gives a higher recurrence rate (10%) and inci-

dence  of  diarrhoea  (20%)  than  does  partial gastrectomy (recurrence  and  diarrhoea  about 3%).  The  more  extensive  operations  leave 

some patients with distressing complications. These  complications  and  their  management are outlined in Table 3.11.

Nausea and vomiting

Definition and aetiology

Nausea is a prodromal symptom, i.e. it is the 

conscious recognition that the vomiting centre 

has been stimulated. Vomiting (emesis) is the 

forcible ejection of stomach contents through 

the mouth.

Vomiting  is  a  common,  usually  benign, 

occasional,  self-limiting  condition,  frequently with an obvious cause. When it occurs with 

diarrhoea, the cause is usually ‘food poisoning’, 

i.e. it is consequent on the ingestion of food or 

drink contaminated with bacteria, bacterial tox-

ins, viruses or, occasionally, protozoa. Migraine, 

pregnancy and the over-consumption of alco-

hol or  food  account  for  many  other  cases.  If 

there  are  no  associated  symptoms,  especially 

systemic ones, the origin may be psychogenic, 

e.g. bulimia nervosa or stress. However, vomiting 

may occasionally be a result of more serious 

disease (Table 3.12).

Vertigo  is  an  extreme,  distressing  form  of 

dizziness in which the patient (or their sur-

roundings), appear to be spinning. Unless of 

very brief duration, vertigo causes vomiting.

The vomiting centre in the brain consists of 

two areas, located symmetrically in the medulla, 

which coordinate the sequence of muscular con-

tractions involved. Additionally, the chemore-

ceptor trigger zone (CTZ), which consists of 

twin areas in the floor of the fourth ventricle, 

partially outside the blood-brain barrier, detects 

noxious ingested chemical stimuli and may be 

stimulated directly by parenteral drugs.

Central and afferent signalling involves sero-

tonin at 5-HT3 receptors, dopamine at D2 recep-

tors, acetylcholine at muscarinic receptors and histamine at H1-receptors, hence the large range of anti-emetic drugs in use:

•  Specific  5-HT3  antagonists:  e.g.  dolasetron,

granisetron, ondansetron, tropisetron.

•  D2 antagonists:

-  Phenothiazines,  e.g.  chlorpromazine,  pro-

chlorperazine, thiethylperazine.

-  Butyrophenones, e.g. droperidol, haloperidol.

-  Benzimidazoles, e.g. domperidone.

-  Substituted   benzamides(trimethobenza-

mide, not UK-licensed).

•  D2/5-HT3 antagonists, e.g. metoclopramide. •  Cannabinoids: dronabinol, nabilone.

•  Antimuscarinics: hyoscine (scopolamine). 

•  Antihistamines:   e.g.   cinnarizine,   cyclizine,

dimenhydrinate, meclozine and promethazine. •  Corticosteroids, e.g. dexamethasone.

Management

General considerations

The occasional episode requires no treatment 

except rest, abstinence from food or alcohol and frequent small amounts of carbonated drinks, as seems appropriate.

In   persistent   nausea   and   vomiting   of 

unknown origin it is essential to find the under-

lying cause and to treat that appropriately. The use of anti-emetics in the absence of a definitive diagnosis may mask symptoms and result in a failure to recognize serious disease. However, many patients demand anti-emetics to avoid dis-

comfort or social embarrassment, but this should not preclude prior investigation.

It is always preferable to give medication in 

anticipation of symptoms, if that is possible, 

rather  than  to  treat  established  vomiting. 

Anticipatory medication is especially important 

in  the  management  of  iatrogenic  vomiting, 

notably from cancer treatment. Once vomiting 

has  started,  particularly  if  it  is  moderate  or 

severe, the oral route clearly cannot be used, and 

rectal (suppositories),  buccal  or  parenteral 

administration  is  needed.  Doses  adequate  to 

control the vomiting are essential, otherwise the 

patient’s confidence in their carers and their 

treatment will be undermined.

Acupuncture  or  transcutaneous  electrical 

nerve stimulation (TENS; see Chapter 7) of the P6 anti-emetic point may be a useful adjunct to pharmacotherapy in some patients.

The neurokinin 1 receptor antagonist aprepi-

tant has been introduced fairly recently for the management of nausea cause by cisplatin-based chemotherapy  resistant  to  other  treatments, used as an adjunct to dexamethasone and a 5-HT3 antagonist.  It  has  numerous  gastrointestinal, cardiac and CNS side-effects.

Vestibular disorders

Motion sickness

This is best controlled with drugs that act at the 

vomiting centre, notably hyoscine (scopolamine). 

Hyoscine is available as tablets, slow-release tablets 

and a transdermal formulation. The latter two 

formulations may help to minimize the antimus-

carinic side-effects of hyoscine, i.e. drowsiness, 

blurred vision, dry mouth and urinary retention, 

and confusion in the elderly, by avoiding the 

peak concentrations that occur with repeated 

oral  dosing.  Hyoscine  is  contra-indicated  in 

patients with closed-angle glaucoma and should 

be used with caution in elderly patients and in 

patients  with  cardiovascular  disease,  urinary 

retention, gastrointestinal obstruction and renal 

or hepatic impairment.

In these patients, or if the side-effects cannot 

be tolerated, one of the sedating antihistamines 

(H1-antagonists such as cinnarizine, cyclizine and 

promethazine), are less likely to cause side-effects 

(apart from drowsiness), but are less effective. 

The first dose should be taken 30 min before 

the  journey  commences  (2 h  for  cinnarizine).

Promethazine is very sedating and should not be 

used if this might create problems, e.g. if driving, 

though sedation may be useful in some cases, 

e.g. with children or at night. Other anti-emetics 

act selectively on the CTZ and are ineffective 

in  motion  sickness.  Alcohol  potentiates  the 

sedative effects of all the drugs used for motion 

sickness.

The hyoscine patches are applied to non-hairy 

skin  behind  the  ear 5-6 h  before  starting  a 

journey. The patches need replacing after 72 h 

and  the  sedation  lasts  for  up  to 24 h  after 

removal,  so  patients  must  be  warned  against 

driving  soon  after  removing  a  patch.  It  is 

essential to wash hands thoroughly after han-

dling a patch, to avoid accidental eye contam-

ination  with  hyoscine,  which  can  cause  fixed 

dilatation of the pupil and paralysis of visual 

accommodation.

Ménière’s disease

This is associated with idiopathic dilatation of 

the endolymph system of the inner ear. It causes 

recurrent   attacks   of   vertigo,   deafness   and 

tinnitus (a subjective sensation of noise gener-

ated within the auditory system), associated with 

nausea and vomiting. Over a period of years the 

disease progresses to permanent deafness, and 

the vertigo remits.

Betahistine reduces endolymph pressure in the 

inner ear and so is used in treatment, with vari-

able benefit. A diuretic, with or without salt 

restriction, may be helpful and could be used as 

a basis for other treatments, but is of doubtful 

value.

In an acute attack, the antihistamine cyclizine 

or the phenothiazine, chlorpromazine, which can 

be given rectally or by IM injection, may be use-

ful. However, the latter may cause prolonged 

sedation and should not be used if this is likely 

to be a problem. Other phenothiazines that may 

help include perphenazine, prochlorperazine  and 

trifluoperazine.

Other drugs, e.g. cinnarizine and hyoscine, may also be beneficial. If the symptoms are distress-

ing and refractory to treatment, surgical ablation of the auditory apparatus is sometimes done. 

This may relieve the vertigo, but it clearly causes deafness on the affected side and tinnitus often remains, and may be severe.

Vomiting in pregnancy

Generally,  nausea  and  vomiting  in  the  first 

trimester can be tolerated and drug treatment is 

usually contra-indicated because of the risk of 

teratogenicity.  In  common  with  other  drugs, 

anti-emetics should be avoided in pregnancy, 

especially in the 3rd to 11th weeks, but in rare 

cases of severe vomiting promethazine, or occa-

sionally metoclopramide or prochlorperazine, may 

be used in the short term (24-48 h), although 

they should preferably be used under specialist 

obstetric supervision.

Iatrogenic vomiting

This is most commonly associated with cancer 

chemotherapy and Parkinson’s disease. Patients 

vary considerably in susceptibility to potentially 

emetogenic drugs. Emesis tends to increase with 

repeated exposure, though whether this is due to 

psychological factors, e.g. reinforcement of the 

unpleasant experience, or intrinsically increased 

sensitivity, is unclear.

The British National Formulary (BNF) lists three classes of potentially emetogenic antineoplastic drugs and procedures but this depends on dosage and patient factors (see Chapter 10):

•  Highly   emetogenic:   cisplatin,   dacarbazine, 

high-dose cyclophosphamide.

•  Moderately emetogenic: doxorubicin, low to 

moderate  doses  of  cyclophosphamide,  high-

dose methotrexate (0.1-0.2 g/m2), mitoxantrone (mitozantrone).

•  Mildly   emetogenic:   etoposide,   fluorouracil, 

methotrexate( 0.1 g/m2),   vinca   alkaloids,

abdominal radiotherapy.

Anticipatory vomiting  is best managed by 

prevention of acute vomiting during treatment, 

e.g. pretreatment with a phenothiazine or dom-

peridone, continued for up to 24 h afterwards. For 

more  susceptible  patients,  dexamethasone  and 

lorazepam can be added beforehand. The latter 

has sedating, anxiolytic and amnesic properties, 

so patients have no memory of the unpleasant 

treatment. High-risk patients will need a 5-HT3 

antagonist (see below).

Delayed vomiting, occurring more than 24 h 

after treatment has ceased, is best managed with

dexamethasone, with or without metoclopramide or prochlorperazine.

The neurokinin 1 receptor antagonist, aprepi-

tant, is licensed for the management of acute and delayed vomiting associated with cisplatin cyto-

toxic chemotherapy.

Drugs used to treat Parkinson’s disease (see 

Chapter 6), e.g. levodopa and dopamine agonists 

(such as apomorphine, bromocriptine, lisuride and 

ropinirole)  are  very  liable  to  cause  vomiting. 

Selegiline, which increases the level of dopamine 

by inhibiting monoamine oxidase-B, has simi-

lar effects. The treatments outlined above are 

appropriate.

Metoclopramide has a wide spectrum of activity, 

and  part  of  its  usefulness  derives  from  its 

enhancement of gastric motility, so hastening 

gastric emptying: an empty stomach reduces the 

volume of vomit, even if it does not abolish the 

reflex. High doses (maximum in 24 h, 20 times 

normal) are used in the short term to prevent 

vomiting induced by cytotoxic chemotherapy. 

The  side-effects  of  metoclopramide  resemble 

those of phenothiazines such as prochlorperazine, 

especially extrapyramidal symptoms, i.e. those 

due to dopamine blockade, but are usually less 

severe.  Prolonged  administration  is  undesir-

able,  as  it  may  cause  tardive  dyskinesia  and 

hyperprolactinaemia, the latter causing sterility.

Domperidone  has  similar  uses  but  does  not 

readily cross the blood-brain barrier, although it 

acts at the CTZ, and so is less likely than the 

phenothiazines to cause central effects, such as 

sedation  and  extrapyrimidal  symptoms.  It  is 

useful in treating nausea and vomiting caused 

by  levodopa,  without  antagonizing  its  anti-

parkinsonian effect.

Nabilone, a synthetic cannabinoid, is reported 

to be superior to prochlorperazine, but is more 

likely to cause side-effects, e.g. hypertension, 

heart disease and psychiatric disorder, so treat-

ment  with  it  is  best  confined  to  hospitals. 

Because it may be neurotoxic, repeated or chron-

ic use may be inadvisable. Nabilone may be used 

for intractable vomiting unresponsive to other 

anti-emetics. The related compound dronabinol is 

used in the USA.

The5-HT3receptor-blocking   drugs, 

dolasetron, granisetron, ondansetron and tropisetron, 

are a relatively new group of anti-emetics. They are used for the control of post-operative nausea 

and  vomiting  and  that  caused  by  cytotoxic 

chemotherapy and radiotherapy, and are the 

most   effective   agents   for   this   purpose. 

Palonosetron is licensed only for the treatment 

of vomiting caused by moderately or highly 

emetogenic cytotoxic therapy. Because of their 

specificity for 5-HT3  receptors this group has a 

relatively good adverse effect profile, the princi-

pal side-effects being headache, constipation and 

rashes, though hypersensitivity reactions have 

occurred. A combination of ondansetron  with 

dexamethasone has been shown to be more than 

twice as effective as ondansetron alone in con-

trolling  severe  vomiting  induced  by  cisplatin. 

Nevertheless,  single  agents  are  preferred  in 

moderate emesis.

All of these 5-HT3 receptor blockers are consid-

erably more expensive than other agents and are used as first-line drugs only in oncology and 

intractable vomiting.

Corticosteroids

Dexamethasone (see above) has been reported to 

be as effective as ondansetron in controlling the 

acute emesis caused by moderately emetogenic 

cytotoxic  chemotherapy,  and  is  the  drug  of 

choice   for   preventing   delayed   vomiting. 

However, the basis for this, and the most effec-

tive dose and route, are unclear, though it may 

have actions at both D2  and 5-HT3  receptors. 

Moderately high IV doses are often used by infu-

sion in cancer chemotherapy because an IV line 

is often already set up to ensure good hydration 

and renal drug clearance.

Anti-emetic adjuncts

Benzodiazepines, e.g. lorazepam, are useful for the   management   of   cytotoxic   drug-induced emesis, because they have sedative, anxiolytic and amnesic effects (see above).

Problems of the small and large intestine

 Malabsorption

Definition

This is a syndrome of numerous diverse origins 

resulting in failure to absorb dietary nutrients. 

The term is usually used to describe a global 

failure of absorption, and is not usually applied 

to a failure to absorb specific substances, e.g. 

vitamin B12.

Common causes are gluten enteropathy (see 

below), Crohn’s disease of the small intestine 

(p. 114), bacterial overgrowth and gastric or 

small-bowel surgery. Less commonly, pancreatic, 

hepatic or biliary disease, or chronic Giardia 

intestinalis (formerly G. lamblia) or other infec-

tions (see  Chapter 8),  may  be  responsible. 

However, any condition causing chronic diar-

rhoea may lead to malabsorption.

Malabsorption may also be drug-induced. The 

lipid-regulating drugs colestyramine and colestipol 

bind bile salts and so may cause a failure to absorb 

dietary lipids. If these anion exchange resins are 

continued long term there may be an associated 

failure to absorb fat-soluble vitamins, so supple-

ments of vitamin A, D and K may be required. 

Orlistat also reduces lipid absorption, with similar 

potential  consequences.  Some  broad-spectrum 

antibiotics, notably those that cause antibiotic-

associated  colitis  (pseudomembranous  colitis, 

AAC; see Chapter 8), may also cause metabolic 

disturbances.

Clinical features

Generalized malabsorption commonly presents 

as chronic diarrhoea, often with steatorrhoea, because  failure  of  absorption  increases  the 

concentration  of  the  bowel  contents  and  so 

causes  an  osmotic  diarrhoea (p. 129).  Other 

gastrointestinal symptoms are abdominal cramps, 

borborygmi (bowel noises), flatulence, bloating 

and a swollen abdomen. However, nutritional 

symptoms may predominate (Table 3.13).

Gluten enteropathy (coeliac disease)

Epidemiology and aetiology

This is the most common cause of malabsorp-

tion in the UK (prevalence about 0.5-1/1000). It 

is about twice as common in Ireland but very 

rare in Africa, possibly related to the high-fibre 

diet there.

Patients  are  hypersensitive  to  the  alpha-

gliadin fraction of gluten, the protein in wheat, 

barley and rye flour that confers the physico-

chemical properties that make dough suitable for 

bread-making. Gluten enteropathy appears to be 

the result of an inherited hypersensitivity state, 

there  being  an  association  with  hyperthy-

roidism,  insulin-dependent  diabetes  mellitus 

and dermatitis herpetiformis (see below). The 

jejunal plasma cells are IgA-deficient, there is an 

association  with  the  MHC  antigens  HLA-B8, 

DR3 and DQW2 (see Chapter 2), and splenic 

lymphoid tissue degeneration occurs.

Coeliac disease may mimic many other dis-

eases, and a diagnosis may sometimes be reached only after a long period of progressive elimina-

tion of dietary components and unsuccessful 

treatment for other suspected conditions.

Clinical features and histopathology

Administration of alpha-gliadin or gluten chal-

lenges  to  predisposed  individuals  results  in 

shortening and eventual atrophy of the jejunal 

villi (Figure 3.14). This effect commences about 

4h after ingestion, the mucosal damage being 

evident within 24 h. This time course and other 

factors  point  to  a  type  III  hypersensitivity 

reaction.

In  susceptible  infants  the  disease  usually appears as soon as cereals are introduced into the diet, causing abnormal stools, failure to thrive and occasionally vomiting. If the disease presents in later life, the diagnostic problems are consider-

able, e.g. adults may present with breathlessness and fatigue, consequent on anaemia. A definitive diagnosis can only be made by:

•  Demonstrating the presence of IgA antibodies 

against gliadin, transglutaminases in tissues

(tTG), and the endomysium, the thin network of fibrils surrounding all muscle fibres, and reticulin;

•  jejunal or duodenal biopsy;

•  remission  of  symptoms  with  gluten  exclu-

sion   and   relapse   on   challenge   with   its

reintroduction.

Management

Management requires lifelong abstinence from 

gluten consumption. This is more difficult than 

may  appear,  because  many  processed  foods 

contain gluten, or wheat or rye flour, as texture

improvers. Gluten-free diets are prescribable in the UK through the NHS, and malabsorption is one of the rare indications for multivitamin 

therapy   plus   minerals.   Following   diagnosis, patients may need to persist with the diet for 

at least 3-6 months before symptoms remit, 

though most respond more quickly.

Some 20% of patients fail to respond satisfac-

torily, because of:

•  exquisite  sensitivity  to  residual  traces  of 

gluten in the diet;

•  poor compliance to the severe dietary restric-

tion involved;

•  very extensive small-bowel involvement; •  pancreatic disease;

•  malignancy.

Some of these problems may improve with 

corticosteroid therapy.

Complication: dermatitis herpetiformis

This is a rare, intensely itchy, burning, blistering 

sub-epidermal condition in which 70% of affected 

patients  have  associated  gluten  enteropathy. 

Malabsorption and the changes in the jejunal

 mucosa are usually less severe than in primary gluten enteropathy without skin involvement. The condition mostly affects adults aged 30 to 50, men more so than women, and follows a chronic, sometimes relapsing course.

Lifelong  gluten  avoidance  is  usually  indica-

ted, and this benefits both the skin condition 

and the malabsorption, though skin improve-

ment may not be seen for 6 months or more. 

The  rash  is  associated  with  the  deposition  of 

antigen-IgA complexes in the skin and responds 

to  dapsone,  which  stimulates  neutrophil  and 

lymphocyte  activity.  Because  patients  with 

glucose-6-phosphate  dehydrogenase (G6PD) 

deficiency  develop  haemolytic  anaemia  with 

dapsone and patients are often anaemic due to 

malabsorption, any anaemia or blood dyscrasia 

should  be  treated  before  starting  dapsone 

treatment. Gluten avoidance spares the dose of 

dapsone required.

Topical steroids are of no benefit alone, but 

combinations with antimicrobial agents may be a 

useful adjunct to prevent secondary infection of 

intensely itchy scratch sites. Colestyramine may 

also help, possibly by binding IgA in the gut, but 

is likely to exacerbate intestinal symptoms.

Saccharide intolerance

Most patients in this group suffer from disac-

charidase deficiency, so lactose (milk and milk 

products), sucrose, maltose or iso-maltose in the 

diet are not absorbed in the small bowel and 

high concentrations of these occur in the colon. 

This causes an osmotic diarrhoea (p. 129), with 

distension and flatulence. Treatment involves 

lifelong   abstinence   from   contact   with   the 

disaccharides and the use of glucose or fructose.

Monosaccharide  intolerance  is  rare  and 

requires lifelong avoidance of glucose, galactose 

or fructose, and substances that yield these on 

digestion, e.g. sucrose and lactose, as appropriate.

Some nutritional deficiencies

Vitamin D deficiency

Simple vitamin D deficiency is usually caused by 

inadequate exposure to sunlight and is treated 

with small doses of ergocalciferol, e.g. 20 lg (800 

units) daily. This is normally in the form of 

calcium and ergocalciferol chewable tablets, up 

to two daily.

However, malabsorption may cause excessive 

losses of the fat-soluble vitamin D and, because 

vitamin D is essential for the uptake and utiliza-

tion of calcium, defective bone mineralization 

and deformity may occur, i.e. rickets in chil-

dren, osteomalacia in adults. Provided that the 

patient has normal kidney function and an ade-

quate dietary calcium intake, high-dose ergocal-

ciferol, i.e. up to 1.25 mg (50 000 units) daily 

may be needed. In cases of severe deficiency an 

oily IM injection is available. Patients taking 

these high doses should have their plasma calci-

um levels monitored regularly, to avoid hyper-

calcaemia. The early signs of this are nausea and 

vomiting,  but  central  nervous,  cardiovascular 

and renal symptoms and bone pain may ensue. 

Because vitamin D is excreted in milk, pregnant 

and breastfeeding women should not indulge in 

the casual consumption of calcium and vitamin 

D, which may cause hypercalcaemia in infants.

People eating diets high in unprocessed bran may  become  hypocalcaemic  due  to  calcium phosphate binding by phytic acid.

Iron and folic acid deficiencies, and anaemia, are discussed in Chapter 11.

Inflammatory bowel disease

Inflammatory bowel disease (IBD) comprises two 

distinct  diseases:  Crohn’s  disease (CD)  and 

ulcerative colitis (UC). Because the former can 

occur anywhere in localized sites in the GIT, 

from the mouth to the anus, the term ‘regional 

enteritis’ has been used. UC is confined to the 

large bowel and may be difficult to distinguish 

from CD restricted to the colon, except by biopsy. 

Although quite different, these conditions share 

many features and are considered together here, 

emphasizing important distinctions.

Three further conditions are now recognized: 

microscopic UC, microscopic collagenous colitis 

and microscopic lymphocytic colitis. These are 

diagnosed on sigmoid biopsy. They present with 

a mild episodic or chronic diarrhoea and, in very 

general terms, are treated similarly to CD and 

UC. They will not be discussed further here.

Aetiology

The causes of both CD and UC are unknown. 

Infective, immunological, dietary and psychoso-

matic  causes  have  been  suggested,  but  until 

recently there has been no evidence for any of 

these.

A possible association has been found with 

Mycobacterium  paratuberculosis,  measles  and 

mumps infections: children who contract both 

of the latter in the same year appear to be up to 

seven times more likely to develop IBD some 20 

years later. A causal link has not been demon-

strated, but there is ongoing research into the 

association  between  M.  paratuberculosis (see 

below) and measles. The research was related to 

natural infection with wild viruses and not to vac-

cination  with  measles/mumps/rubella  vaccine, 

which is safe.

There is an inherited predisposition to an abnor-

mal response to environmental agents, especi-

ally in CD, as there is familial clustering. The 

association between IBD, ankylosing spondylitis and  the  histocompatibility  antigen  HLA-B27 suggests some autoimmune component. Known associations in first-degree relatives are:

•  About 50% concordance rate in monozygotic 

twins,  but  this  implies  an  environmental

trigger.

•  The relative risk of occurrence of CD in first-

degree relatives compared with more distant

relatives is about 12, and in UC is about 8. 

The lower figure for UC implies that environ-

mental factors are more important than in 

CD. There is also an influence on the type of IBD that occurs, i.e.

-  similar clinical course;

-  sites of CD in the gut.

Additional known genetic associations are:

•  Between CD and genes on chromosomes 7, 12 

and 16.

•  Between UC and HLA-DR1*103.

•  In Japanese patients, between UC and HLA-

DR2.

•  Between   cytoplasmic   antineutrophil   anti-

bodies (cANCA) and 70% of patients with UC

and granulomatous vasculitis in CD.

In addition, environmental factors that may 

be implicated are:

•  Infection:  viruses  and  bacteria  (including

bacterial L-forms). Apart from the measles and

mumps  viruses  reported  above,  the  most 

promising  candidate  is  M.  paratuberculosis, 

which causes Johne’s disease in sheep and 

cattle, involving inflammation of the distal 

ileum. It is interesting that these animals only 

develop Johne’s disease if they are infected by 

the mycobacteria as juveniles, though symp-

toms occur only in fully-grown adults. This 

could account for the inability to isolate the 

organism from human CD patients. Further, 

some patients improve after antitubercular 

therapy.

•  Consumption of refined sugar and diets high 

in fibre.

•  Smoking:  CD  occurs  more  commonly  in 

smokers, whereas UC, curiously, is often asso-

ciated with smoking cessation and is twice as common in non-smokers. Further, nicotine is effective in treating UC.

 The basic question to be answered is the mech-

anism by which an initial infection or other 

insult is translated into a continuing autoim-

mune reaction after an interval of some 20 years. This problem relates to diseases other than IBD, e.g. RA (Chapter 12).

Recent  genetic  studies  have  significantly 

advanced our understanding of the basis of CD 

and provide a link to the infective theory of cau-

sation. About 15% of patients have homozygous 

mutations of one of two genes (CARD15 and 

NOD2),  which  are  often  associated  with 

fibrostenotic ileal disease (see ‘string sign’ below).

The NOD2 gene is expressed in cells in the 

intestinal  crypts,  macrophages  and  other 

phagocytic cells. Its product is involved in the 

innate  immune  system (see  Chapter 2)  and 

detects  microbial  components,  triggering  pro-

inflammatory cytokine secretion and recruiting 

phagocytic leucocytes to promote their removal. 

The  precise  mechanisn  by  which  the  genetic 

defect is translated into continuing inflammation 

is unclear. There may be reduced microbial clear-

ance, an impaired intestinal barrier to infection 

or reduced leucocyte chemotaxis to the inflamed 

sites. An increased sensitivity to microorganisms 

or  their  metabolic  products  may  also  occur, 

predisposing to enhanced inflammation.

However, not all individuals with NOD2 muta-

tions develop CD, so other predisposing genetic 

factors are likely to be involved. Nevertheless, 

ongoing  genetic  research  promises  major 

advances in our knowledge of the aetiology of 

IBD and consequent improvements in treatment.

Epidemiology

Both CD and UC occur throughout the world, 

and affect all races and both sexes. However, the 

incidence is generally higher in developed coun-

tries, especially in Northern Europe. Although 

we have noted an interaction between genetic 

and  environmental  influences,  possibly  diet, 

attempts to link IBD with a lack of dietary fibre 

have been disappointing. The true incidence in 

the subtropics and tropics is unknown, because 

IBD may be difficult to distinguish from infec-

tive diarrhoeas, including bowel TB. Thus a trial 

of antitubercular therapy may be appropriate if 

laboratory  investigation  of  biopsies  is  not 

readily available. Jews of central European origin 

seem to be about twice as liable as the general 

population to suffer from IBD, especially CD.

CD  has  a  UK  annual  incidence  of  about 

6/100 000,   with   a   prevalence   of   about 

50-100/100 000,  the  figures  for  UC  being 

about twice as high. There was a rapid increase 

in the incidence of CD between 1955 and 1975, 

but this may have stabilized. The reasons for 

this are unknown, but an increase in the con-

sumption  of  processed  foods  may  have  been 

responsible.

CD often occurs initially at a mean age of 

about 26 years, and is a little more common in 

females,  whereas  UC  usually  commences  at 

about 34 years and is equally common in both 

sexes. The 15- to 40-year age group is mainly 

affected and there is a second peak with UC at 

55-70 years, but both diseases can occur at any 

age.

Pathology

CD  usually  affects  the  terminal  ileum  and 

ascending colon (70% of cases). The inflamma-

tion is transmural (i.e. affects the whole thick-

ness of the bowel wall), and often involves the 

mesentery and lymph nodes, causing adhesions 

between loops of bowel. Epithelial ulceration is 

discontinuous and ulcerated areas are separated 

by patches of oedematous or apparently normal 

tissue, producing a ‘cobblestone’ appearance of 

the gut lining. This gives rise to what are known 

as ‘skip lesions’ (Figure 3.15). The affected bowel 

is hard, rubbery and narrowed, with a small 

lumen (the ‘string sign’) and eventually becomes 

fibrosed.

The rectum is involved in over 90% of cases of 

UC, and inflammation may spread to involve 

the sigmoid and descending colon and, in severe 

cases, the whole of the colon (pancolitis). It may 

also affect the terminal few centimetres of ileum, 

though this is unusual. Unlike CD, only the 

mucosa and submucosa are affected, and contin-

uously with no skips along the infected area. 

Severe disease is usually chronic, rather than 

episodic, and may result in toxic dilatation of 

the colon and perforation.

Clinical features

These will clearly depend on the site, extent and 

severity of active disease. The outstanding symp-

toms of both diseases (Table 3.14) are diarrhoea, 

unless UC is confined to the rectum or CD 

affects only the upper GIT. Fever, abdominal 

pain,  malaise,  lethargy  and  weight  loss  also 

occur.  In  UC,  the  diarrhoea  is  bloody  and 

contains mucus. Acute attacks may be triggered 

by infections, the use of NSAIDs and severe 

stress.

Crohn’s disease

Because CD can affect any part of the GIT, the 

symptoms  largely  reflect  dysfunction  of  the 

affected region. Some patients may have only 

mild discomfort or may even present with general 

malaise,  unaccompanied  by  gastrointestinal 

symptoms.  About  80%  of  patients  have  diar-

rhoea. Onset may be acute or insidious. Severe 

malabsorption,  leading  to  hypoalbuminaemia 

and consequent peripheral oedema, may occur 

when the ileum is affected and cause growth 

retardation in children. Recurrences are common 

(50%  in  10  years),  although  the  relapse  rate 

decreases the longer the disease-free interval.

Many   patients   present   with   an‘acute 

abdomen’ resembling appendicitis, with pain in the right iliac region.

Complications

A unique feature of CD is the tendency to cause adhesions,  including  perforation,  and  fistula formation may occur (a fistula is an abnormal connection between internal organs or between an internal organ and the skin surface); perianal abscesses may precede the onset of more general symptoms by some years.

Fistulae are especially troublesome in small bowel and perianal disease. The occurrence of prodromal perianal abscesses has already been mentioned, and rectal and anal lesions cause 

considerable  distress,  as  do  fistulae  into  the bladder or vagina. Failure of bile salt resorption may exacerbate diarrhoea and cause cholesterol gallstones and oxalate kidney stones.

Extragastrointestinal features are common and 

include mouth ulcers, rashes, finger clubbing (see Chapter 5), eye problems (7% of patients), 

joint pain (14%), inflammatory arthritis (10%) 

or ankylosing spondylitis (9%), gallstones (up to 

30%),  kidney  stones (in  patients  with  small 

bowel  disease)  and  skin  rashes (5%).  Rare 

complications include toxic megacolon, bowel 

perforation, renal and liver disease and amyloid 

disease (see Chapter 12). Many patients have

several of these complications. Obstruction may accompany ileocaecal disease.

There is a slightly increased risk of colon can-

cer if the colon is markedly involved, but this is very much less than in UC (see below).

Complications are frequently associated with 

exacerbations of the gastrointestinal symptoms. 

Despite this long catalogue of possible symptoms, patients  sometimes  present  with  unexplained weight loss as the sole symptom.

Ulcerative colitis

Diarrhoea in acute UC may be very severe, with 

10-20  watery,  bloody  motions  with  mucus 

occurring throughout a 24-h period. However, 

disease confined to the rectum may cause severe 

constipation. The disease may present with mild 

symptoms, especially if restricted to the rectum 

and the sigmoid colon, but severe cases may be 

life-threatening.

Complications

Severe  diarrhoea  may  cause  dehydration  and 

malabsorption  with  hypokalaemia,  metabolic 

acidosis,   anaemia,   weight   loss,   hypoalbu-

minaemia and oedema. Skin lesions, large joint 

inflammatory  arthritis,  toxic  megacolon  and 

biliary tract disease, including carcinoma, may 

occur.  Patients  with  long-standing  disease  (10 

years), and those in whom a pancolitis has ever 

occurred, have a greatly increased risk of bowel 

perforation and carcinoma of the colon.

Diagnosis

This requires a careful history and examination. 

Investigations include a full blood count, ESR, 

electrolytes, barium meal and follow-through,

 double-contrast barium enema, sigmoidoscopy and/or   colonoscopy   and   biopsy,   and   stool cultures. CD patients may show characteristic changes in the sigmoid colon even if it is not 

apparently involved.

Both diseases may be difficult to diagnose and distinguish from other causes of chronic diar-

rhoea, unless there is a high index of suspicion, or the patient’s condition is severe and charac-

teristic. Some diseases that may be confused with IBD are given in Table 3.15.

Management

Aims

The aims of management include:

•  rapid symptom relief and prompt control of 

acute attacks;

•  correction of metabolic disturbances; 

•  prevention of serious complications;

•  long-term  immunosuppressive  and/or  anti-

inflammatory, prophylactic or maintenance therapy (for some patients);

•  anticipation of the need for surgery and, if 

possible, avoidance of emergency procedures.

Both diseases are treated somewhat similarly. 

Because there is considerable variation in pre-

sentation and the severity of their symptoms, 

only very general guidelines can be given here. 

The precise approach will depend on the con-

dition  and  response  of  each  patient,  and  the likelihood of serious complications.

Clearly, any aspects of diet or medication that 

may exacerbate the diarrhoea should be rectified.

Nutritional  support  plus  correction  of  fluid 

and  electrolyte  imbalance. Corticosteroids  (see 

below)  may  be  sufficient  for  occasional  acute 

attacks  and  exacerbations.  More  intensive 

pharmacotherapy  is  required  for  those  who 

suffer  frequent  exacerbations  or  chronic 

symptoms.

General measures

Patient  education  about  the  nature  of  their 

disease and its treatment is essential. They need 

to participate actively with their doctors in ther-

apeutic modifications to manage unpredictable 

variations in disease activity. Patients should be 

in the care of a specialized clinic and those with 

moderate to severe disease treated in hospital.

Bedrest may be helpful in debilitated patients. 

CD patients should stop smoking. Stress reduc-

tion is frequently advised, but difficult to follow. 

It is not clear whether stress is a trigger factor for 

exacerbations of the disease or a consequence of 

the symptoms.

In  the  absence  of  precise  knowledge  of 

the  aetiology  of  IBD,  anti-inflammatory  and 

immunosuppressive drugs are the mainstay of 

therapy. These include corticosteroids, immuno-

suppressants, aminosalicylates, biological agents 

(monoclonal  antibodies,  cytokine  inhibitors). 

Antibiotics may be required in CD with perineal 

disease.

Acute attacks and exacerbations

Supportive therapies

A  highly  nutritious,  low-residue  fluid  (‘ele-

mental’) diet, enteral nutrition (i.e. by nasogas-

tric tube), or percutaneous enteral gastroscopy 

(PEG) if there is mouth or oesophageal involve-

ment in CD. This is also needed if a bowel 

stricture is present and obstruction is possible. 

Vitamin supplementation may be required, espe-

cially vitamin B12  and folate in CD that causes 

malabsorption (see Chapter 11 and p. 111). A 

low-fat, low linoleic acid diet is helpful if there is 

steatorrhoea in CD.

 ‘Bowel rest’ does not seem to be beneficial and the concept does not appear to be valid.

Anaemia will usually respond to control of the disease, but oral or parenteral iron, or blood 

transfusion may sometimes be needed.

Pharmacotherapy

Antidiarrhoeal agents, e.g. loperamide or codeine, 

may be needed to control florid symptoms, but 

should be used sparingly because the resultant 

slower clearance of faecal residues may encourage 

the accumulation of pro-inflammatory agents, 

with  symptom  aggravation  and  even  toxic 

megacolon. However, patients need relief from 

frequent defecation, so a balance has to be struck 

between symptom relief and toxic risk.

Corticosteroids are the most effective agents 

and should be used to bring symptoms under 

control promptly in CD, the response rate being 

60-90% depending on disease severity and loca-

tion. Patients with moderate to severe disease 

lose confidence in their physician if they have to 

suffer miserably during trials of less effective 

drugs.

Steroids, used intravenously in severe attacks, may  be  combined  with  aminosalicylates  (see below) or, if the patient has been admitted in the previous 2-3 years  with  moderate  to  severe attacks, azathioprine.

Oral  prednisolone  30-60 mg  daily,  reducing over 6-8 weeks, is widely used, with or without azathioprine  or its metabolite, 6-mercaptopurine (see below). In severe cases IV hydrocortisone or methylprednisolone  therapy is used, e.g. up to 100 mg hydrocortisone 6-hourly.

Corticosteroid  retention  enemas  are  useful 

in  CD  only  for  rectal  or  distal  colonic  dis-

ease.  Mild  to  moderate  CD  confined  to  the 

ileum and ascending colon may get adequate 

benefit  from  oral  modified-release  budesonide. 

This  has  high  topical  potency  and  undergoes 

extensive  first-pass  metabolism,  so  adverse 

effects are less common and severe than with 

other corticosteroids.

In  UC,  corticosteroids  are  used  to  obtain 

remission in moderate to severe attacks or as an 

adjunct   to   aminosalicylates(see   below). 

Corticosteroid retention enemas or rectal foams 

are used routinely for UC and spare the systemic 

corticosteroid dose.

Immunosuppressants.   Azathioprine,    or    its 

metabolite mercaptopurine, is used, especially in 

CD and moderate to severe UC for its steroid-

sparing effect. It is ineffective as sole therapy in 

active disease and should be given promptly in 

severe  disease,  e.g.  pancolitis (affecting  the 

whole colon), as it takes several weeks to exert its 

effect. They are suitable for long-term mainte-

nance therapy, but there is a high relapse rate on 

discontinuation.

Methotrexate and IV ciclosporin, a calcineurin 

inhibitor, have been used to manage disease 

resistant to steroids and other immunosuppres-

sants. They are effective in producing remission 

but not for maintenance therapy. Mycophenolate 

mofetil, given intravenously only, has been used 

similarly (unlicensed indication). It is effective in 

severe, steroid-resistant UC, being used initially 

as an IV infusion, transferring to oral use for 

maintenance. It may avoid the need for surgery 

or give time for surgery to be planned as an elec-

tive procedure, but this must be weighed against 

the risks of serious complications occurring as a 

result of delay.

Aminosalicylates.   These include sulfasalazine (SSZ), the original member of this group, which is a salt formed between sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA); olsalazine (a dimer of 5-ASA); mesalazine (modified-release 5-ASA); and balsalazide (5-ASA linked by a diazo bond to 4-aminobenzoyl-beta-alanine, a carrier that has no pharmacological effect, unlike SP).

SSZ is not absorbed in the small intestine, and 

the SP acts as a carrier to deliver 5-ASA to the 

colon, where the SSZ is split by bacterial action, 

though the validity of this assumption has been 

questioned. The SP and some 5-ASA are subse-

quently absorbed, but about 50% of the 5-ASA 

remains  in  the  colon  to  exert  a  local  anti-

inflammatory effect. SSZ is less widely used now 

than other aminosalicylates because of its poorer 

side-effect profile, due to the absorbed SP (see 

below).

Oral  mesalazine  is  specially  formulated  for 

large  bowel  release,  in  an  attempt  to  avoid 

absorption of 5-ASA from the small intestine. 

However, the time to reach the ileocaecal junc-

tion  and  the  ileal  residence  time  are  very 

variable, due to disease activity, both between

 individuals and in the same patient at different times, so the extent to which 5-ASA release is confined  to  the  large  bowel  is  unpredictable. This may explain some failures of therapy. It 

is  licensed  for  the  oral  treatment  of  mild  to moderate UC and to maintain remission.

Olsalazine is similarly split by colonic bacteria 

to yield only 5-ASA and is licensed to treat mild 

UC and maintain remission. Balsalazide is a pro-

drug of 5-ASA and resembles SSZ in drug delivery.

The  aminosalicylates  are  used  primarily  to 

induce  and  maintain  remission  in  UC (see 

below), and for maintenance in CD. Olsalazine is 

licensed for use in mild UC, balsalazide  and 

mesalazine for mild to moderate UC. Any of this 

group may be adequate alone in mild attacks 

of  UC,  but  moderate  disease  may  also  need 

corticosteroids.

SSZ is the only member of this group licensed 

for all severities of UC and for active CD, and 

also has a steroid-sparing effect. However, it has 

a limited place in the treatment of severe attacks, 

possibly because its hydrolysis to release 5-ASA is 

unpredictable in the diseased colon. Because of 

its poorer side-effect profile it is being used less 

often than the other aminosalicylates. SSZ may 

occasionally be used to treat active CD confined 

to the distal colon.

Biological agents.   Only one of these, inflix-

imab, is currently used in IBD. It is a chimeric 

murine/human  monoclonal  antibody  against 

the  potent  pro-inflammatory  TNFalpha (see 

Chapter 2). It is used in severe active CD, espe-

cially if there is fistulation, and spares the corti-

costeroid dose. It is also licensed for moderate to 

severe  UC.  However,  it  is  antigenic  and  the 

development of antibodies limits its usefulness. 

Limitations on its use are the need to give it by 

IV infusion and that it may cause severe anaphyl-

actic  reactions,  so  full  resuscitation  facilities 

must be immediately available. It must not be 

used in patients with active TB, which must be 

treated for at least 2 months before initiating 

infliximab treatment. It may also trigger reactiva-

tion from dormant tubercles (see Chapter 8). 

Patients require careful monitoring for TB and 

other infections, which may be severe.

Recent trials have confirmed that infliximab is 

effective in UC. It produces about a 60% response rate at 8 weeks and about a 45% remission rate at

30 weeks. There is also significant mucosal heal-

ing and a steroid-sparing effect. Consequently, 

infliximab is likely to be especially beneficial in 

patients who are unresponsive to corticosteroids 

or are steroid-dependent, and in those who do 

not  tolerate  conventional  immunosuppressive 

treatment.

Adalimumab is a fully human anti-TNF anti-

body that is currently licensed only for use in 

rheumatoid disease (see Chapter 12), but the 

licence is likely to be extended shortly for use in 

CD. It has been shown to produce remission in 

active disease. The most effective regimen, a 

loading  dose  of 160 mg  followed  by 80 mg

2 weeks later, gives a remission rate of about 36% at 4 weeks. These doses are much larger than 

those used for RA. It appears to be effective in those who are not responding adequately to 

infliximab, but it is still antigenic. It has the 

advantage over infliximab that it is given by SC injection rather than by IV infusion, but has the same restrictions regarding infections.

Certolizumab  is  a  new,  as  yet  unlicensed, 

humanised   pegylated   Fab   fragment(see 

Chapter 2)  of  anti-TNF  antibody.  Given  by 

monthly  SC  injection  it  has  achieved  a  53% 

response rate at 10 weeks in one study and a 

63% response rate over 26 weeks in another, in 

which about 48% were in remission. This result 

was not affected by previous treatment or the 

initial  level  of  inflammation,  as  measured  by 

CRP measurement.

Another new monoclonal antibody, natalizum-

ab, is directed against alpha4-integrin, an adhe-

sion molecule expressed on lymphocytes. It pre-

vents lymphocyte adhesion to the endothelium 

of the inflamed intestinal microvasculature and 

so infiltration of lymphocytes into the intestinal 

lumen.  Early  trials  showed  an  impressive 

response in CD patients. It has been withdrawn 

for further safety evaluation following the occur-

rence   of   progressive   multifocal   leucoen-

cephalopathy in two multiple sclerosis patients, 

a serious viral demyelinating CNS disease lead-

ing to paralysis and death. Despite this, natal-

izumab indicates a new and promising potential 

mode of treatment. Because of its novel mode of 

action it should be effective in patients in whom 

anti-TNF therapies have failed.

Antibiotics.   Metronidazole or tinidazole may be 

useful if there is bacterial overgrowth in the 

bowel or if septic complications occur, because 

anaerobes  are  often  involved.  Bowel  perfora-

tion  may  lead  to  peritonitis  and  septicaemia, 

with an urgent need for surgery and parenteral 

antibiotics, after the identification of microbial 

sensitivities.  Co-trimoxazole (trimethoprim  plus 

sulfamethoxazole)  has  been  used  but  is  now 

appropriate  only  for  infections  of  known 

sensitivity that are unresponsive to other agents.

Continuing diarrhoea in well-treated patients 

is not necessarily due to infection, but may be 

due to failure of the diseased small bowel to reab-

sorb bile salts (see Chapter 3). Treatment with 

the anion exchange resin colestyramine is then 

indicated.

Topical rectal treatment.   SSZ and mesalazine 

are available as suppositories. Mesalazine is also 

produced as retention enemas. Some patients 

find  the  large  volume (100 mL)  of  retention 

enemas difficult to use, but mesalazine is also 

available as a small volume foam enema that is 

lighter and better tolerated. These products are 

useful for mild to moderate UC and for CD 

confined to the distal colon and rectum. They 

may spare the steroid dose. The oral and rectal 

preparations are sometimes used together.

Side-effects.   If the SP moiety in SSZ  causes 

unacceptable side-effects, and this is more likely 

in  slow  acetylators,  olsalazine,  balsalazide  or 

mesalazine may prove more suitable. However, 

5-ASA   also   causes   side-effects,   e.g.   nausea, 

headache, rash, and even diarrhoea and occa-

sional  exacerbation  of  colitis.  SSZ  causes  a 

reversible oligospermia and so is unsuitable in 

men wishing to raise a family. The monitoring of 

SSZ treatment is dealt with in Chapter 12.

There have also been occasional reports of 

nephrotoxicity with all aminosalicylates, which 

should be used cautiously in renal impairment 

and during pregnancy and breastfeeding. This is 

due to the absorption of 5-ASA, and mesalazine 

produces higher serum concentrations of 5-ASA 

than the azo-bonded products (SSZ, olsalazine 

and  balsalazide). It is not clear whether this 

nephrotoxicity is due to 5-ASA or to its acetyl 

metabolite,  but  it  seems  prudent  to  reserve mesalazine for mild to moderate UC affecting the distal small bowel and colon.

All   aminosalicylates   may   cause   blood 

dyscrasias, e.g. agranulocytosis, aplastic anaemia, 

leucopenia, neutropenia and thrombocytopenia. 

Patients should be advised to report any unex-

plained bruising, bleeding, sore throat, fever or 

malaise. If any of these occur the drug should be 

stopped and a full blood count done. SSZ may 

also cause a lupus-like syndrome (see Chapter 

12).  They  occasionally  cause  hypersensitivity 

reactions in patients hypersensitive to aspirin 

and other salicylates. However, many patients 

use these drugs without significant problems.

Antidiarrhoeals.   Codeine or loperamide may be 

used cautiously, to relieve discomfort. However, 

they should be avoided as far as possible because 

they tend to cause pooling of fluid in the bowel 

and may aggravate or prolong symptoms. In 

particular, they may induce obstruction in CD 

and  toxic  megacolon.  They  are  not  used  in 

severe attacks: it is preferable to control diar-

rhoea by controlling the disease process with 

corticosteroids etc. (i.e. treat the disease and not 

the symptom).

Experimental agents.   Infusion of IL-10 has 

been used as rescue therapy and helps about 70% of patients with steroid-resistant disease. It is 

expensive and not yet generally available, but may point the way to potentially important 

developments in therapy.

Maintenance therapy

This is standard practice for both diseases, to 

reduce   recurrence.   Prophylaxis   follows   the 

general  lines  of  the  management  of  acute 

attacks, modified suitably according to disease 

activity and the severity of symptoms. In UC, 

maintenance  therapy  reduces  the  untreated 

recurrence  rate  of 80%  at  1  year  by  about 

three-quarters.

Because CD often follows an unpredictable 

relapsing-remitting  course  with  symptom-free 

intervals of several years, it has been common 

practice  not  to  give  maintenance  therapy 

unless  symptoms  recurred.  However,  success 

with high doses of the newer aminosalicylates,

especially mesalazine, has changed this picture. The principal differences are outlined below.

Diet

In   contrast   to   the   management   of   acute 

episodes, a high-residue diet is preferred unless 

there is a possibility of bowel obstruction, e.g. as 

the result of stricture formation. A high-carbohy-

drate, high-protein diet minimizes the possibility 

of  nutritional  deficiency  due  to  chronic  diar-

rhoea.  Vitamin  and  mineral  supplementation, 

especially iron, is often given. Avoiding milk or 

milk products may occasionally be useful in some 

patients, especially those with small-bowel CD 

(p. 131).

Aminosalicylates

SSZ,  or  one  of  the  alternatives  mentioned 

above, are the mainstay of maintenance in UC. 

They reduce the relapse rate by about 75% and 

should be continued for life. Aminosalicylates 

(2 g/day,  or  more  if  tolerated)  are  beneficial 

in  those  with  small-bowel  or  colonic  CD. 

Mesalazine is preferred because it is released in 

the  distal  small  bowel  and  should  be  started 

about 2 months after surgery or relapse, as soon 

as recovery permits. Lactulose and lactitol should 

not be used with enteric-coated and modified-

release  preparations  because  they  acidify  the 

bowel and prevent drug release. However, these 

combinations are rare. Enemas and supposito-

ries  are  used  for  rectal  and  sigmoid  disease 

and  may  spare  the  oral  dose.  Although  SSZ 

frequently  causes  gastric  distress,  and  enteric-

coated  tablets  are  available,  it  is  doubtful 

whether these are beneficial.

Corticosteroids

Retention enemas and rectal foams, and some-

times suppositories, are used for rectal and distal colonic disease.

Chronic small-bowel involvement in CD is 

controlled with minimal oral doses, and intelli-

gent patients should be counselled on judicious 

increases in dose to control exacerbations as 

soon as they occur: enemas may spare the oral 

dose required if CD is confined to the distal 

ileum or colon. However, patients should seek 

medical advice for anything other than mild 

exacerbations.

Oral  corticosteroids  do  not  influence  the 

relapse rate in UC and should be tapered off and 

stopped completely when symptoms remit, to 

minimize side-effects. However, some patients 

are steroid-dependent and relapse as soon as 

dose reduction is attempted. They are normally 

treated  with  azathioprine  or  methotrexate (see 

above) to permit the corticosteroid dose to be 

reduced to the minimum consistent with ade-

quate control. Budesonide may be preferred in 

ileal and ascending colonic involvement.

Immunosuppressants

Azathioprine has a limited role in maintenance therapy for UC. However, it halves the relapse rate in CD and may enable substantial with-

drawal of corticosteroids. If tolerated it should be continued for at least 5 years.

Antibiotics

These should be used promptly for the treatment of any systemic infections, as there is evidence that infections may trigger exacerbations.

Surgery

Surgery is indicated if medical management fails, for the treatment of complications, e.g. toxic 

megacolon,   perforation,   obstruction,   malig-

nancy, and the repair of abscesses or fistulae. A further indication in children is retardation of 

growth   and   development   despite   intensive medical management.

In UC, colectomy is curative, ileoanal anasto-

mosis with formation of a pouch to contain the 

faeces being the preferred procedure. However, a 

permanent ileostomy (p. 134) may be necessary 

at some stage and is the procedure of choice in 

older patients. Colectomy is also carried out as 

an elective procedure in patients who have had 

extensive UC for more than 10 years, or if they 

have ever had a pancolitis, to pre-empt possible 

malignancy.

However, surgery is avoided as far as possible 

in CD, because relapse is common (30% in 5 

years, 50% in 10 years) and repeated surgery is 

debilitating and carries a relatively high cumula-

tive mortality. Thus only minimal surgery to deal 

with complications, e.g. fistula repair, is carried 

out unless there are frequent severe exacerba-

tions. Patients with ileocaecal disease are more 

likely to need surgery than those with colonic or 

other  involvement.  However,  about 80%  of 

patients with CD have surgery at some time.

Prognosis

Nearly all CD patients have chronic or recurrent 

disease, with at least one serious relapse. The 

probability of recurrence is greater if there was 

extensive  initial  disease,  if  perianal  ulceration 

has occurred, or if an ileocolonic anastomosis 

has  been  formed  at  surgery.  The  mortality 

rate  now  approaches  that  for  the  population 

generally,  with  most  deaths  being  associated 

with   extensive   severe   small-bowel   disease, 

onset in the third decade of life and emergency 

surgery.

In UC, some patients have only a single attack, 

but many have mild disease, with proctitis only, 

and the outlook is correspondingly good, the 

overall mortality being near normal. About 10% 

of patients have chronic symptoms, and a fur-

ther 10% have severe attacks requiring surgery. 

Although prompt surgery may be life-saving, 

severe attacks are associated with only about 1% 

mortality if managed in specialist centres (5% 

elsewhere).

Other colonic and rectal disorders

Diverticular disease

Definition

A diverticulum is a pouch projecting from the 

wall of the gut. Diverticula can occur almost 

anywhere from the oesophagus to the rectum 

and may be congenital, e.g. Meckel’s divertic-

ulum in the ileum. Those in the small intestine 

tend to be either asymptomatic or cause only 

vague dyspeptic symptoms, and complications 

are unusual. However, diverticular disease of the 

colon (DDC)  occurs  frequently,  often  in  the 

sigmoid colon where the wall is weakest.

Diverticulosis is the presence of diverticula, 

which may be asymptomatic or produce only mild,   non-specific   abdominal   symptoms.Management

Diverticulitis  is  the  result  of  infection  and

A high-fibre diet, possibly supplemented with a 

inflammation   of   the   diverticula,   causing 

moderate to severe symptoms.

Aetiology

DDC is believed to result from a lifelong lack of dietary fibre, because the disease is common in Western countries but is unusual in rural Africa. In the absence of adequate bulk, intense contrac-

tions  of  bowel  segments  produce  high  local intraluminal pressures and the mucosa and sub-

mucosa  become  ballooned  out  and  herniate through the overlying muscle layers at points of weakness,   usually   where   blood   vessels   and nerves enter the intestinal wall.

The average age at diagnosis is 55 years and 

the incidence increases directly with age, being 

dependent  on  the  loss  of  colonic  muscle 

strength and the duration of the bowel insult. 

Consequently, some degree of diverticulosis is 

present in some 50% of people aged over 60 

years.

Clinical features and diagnosis

Although  diverticulosis  is  usually  asympto-

matic, it is so common that it may be blamed 

for   symptoms   caused   by   other   diseases. 

However, if the diverticula become filled with 

stagnant faecal residues, infection and inflam-

mation  may  cause  diverticulitis.  The  most 

prominent symptom is spasmodic or constant 

pain, usually in the lower abdomen, and espe-

cially  in  the  left  iliac  region.  Flatulence  and 

constipation are common, though diarrhoea may 

also occur. Pain may follow meals and is relieved 

by defecation or passing wind (flatus). In severe 

cases, with numerous large infected diverticula, 

colonic  obstruction  or  abscess  formation  may 

cause severe localized pain (so-called ‘left-sided 

appendicitis’).  Perforation  of  the  bowel  may 

cause peritonitis and septicaemia. Intermittent 

haemorrhage may cause rectal bleeding and a 

misdiagnosis of haemorrhoids.

Diagnosis is by barium enema and ultrasound, but fibre-optic endoscopy may be needed in 

difficult cases.

bulking agent (e.g. bran or ispaghula), is recom-

mended  to  reduce  intracolonic  pressures  and 

to prevent faecal stagnation and constipation, 

which   aggravates   the   condition   due   to 

straining.  Antispasmodics (e.g.  alverine,  dicy-

cloverine, mebeverine, propantheline or peppermint 

oil) may be useful for colic. Antibiotics, e.g. a 

cephalosporin,  with  or  without  metronidazole, 

help with infection. If severely ill, the combina-

tion of gentamicin plus metronidazole is often used. 

Italian trials have found that the combination of 

a rifamycin plus increased dietary fibre was effec-

tive, about 75% of patients being symptom-free 

after 1 year. The equivalent UK-licensed drugs 

would be rifampicin 300-450 mg plus 3.5 g of 

ispaghula husk, both twice daily.

If  pain  is  very  severe,  analgesia  may  be 

provided  with  pethidine.  Morphine  is  contra-

indicated  because  it  reduces  gastrointestinal 

motility,  and  so  aggravates  constipation  and 

increases  intraluminal  pressure.  Related  anti-

motility  drugs (e.g.  codeine,  loperamide)  may 

similarly  aggravate  symptoms  and  are  also 

contra-indicated.

Surgery is occasionally necessary to remove 

large, isolated diverticula or a badly affected sec-

tion of bowel, or to deal with complications, e.g. 

perforation.

Constipation

Definition and aetiology

Constipation  may  be  defined  as  a  reduced 

frequency of defecation, i.e. less frequently than 

is normal for the individual concerned, accom-

panied by difficulty in passing hardened stools. 

There may also be sensations of incomplete defe-

cation and that the rectum remains loaded with 

faeces.

Some possible causes are listed in Table 3.16. 

Defecation is a highly variable function and nor-

mality may range from three motions per day to 

one in 3 days. One of the most common causes 

of constipation is a low-residue, low-fluid diet. 

This may be compounded by poor toilet facili-

ties  or  a  stressful  busy  life,  resulting  in  an unwillingness to defecate or an inability to do so at adequate leisure.

In the elderly, poor muscle tone in the intes-

tine  and  abdominal  wall,  perhaps  associated with  a  lack  of  activity,  depression  and  a  low food  and  fluid  intake,  often  leads  to  faecal impaction. The patient may complain of a hard mass  in  the  left  iliac  region,  or  it  may  be detected on examination.

In young children, constipation may be due to 

inappropriate  diet  or  to  congenital  defects, 

although the latter would be detected by the 

paediatrician or health visitor at an early age. 

However, it is more often the result of emotion-

al  conflict  with (usually)  the  mother.  If  an 

attempt is made to toilet-train children before 

they are ready to accept it, or if the parent 

becomes anxious or obsessive about the prob-

lem, the child may see the withholding of defe-

cation as a strategy for manipulating the parent. 

A 2-year-old  often  behaves  negatively  and  a 

4-year-old aggressively. Either behaviour pattern 

can  result  in  a  vicious  cycle  if  the  parent 

responds inappropriately, leading to the regular 

withholding of bowel motions and the start of 

chronic constipation.

Another common pattern is the reaction to a 

clinging, fearful child with over-permissiveness 

and over-indulgence. Moreover, if parents have 

incorrect ideas about what constitutes ‘proper’

bowel function, children may learn unsuitable behaviour, for example that ‘tummyache’ leads to illness and headache - symptoms that may be rewarded with over-protectiveness, presents and time off school. All these childhood behaviour patterns can persist into adult life.

Clearly, any condition that leads to pain on 

defecation, notably haemorrhoids, will lead to 

reluctance to evacuate the bowel and thus to 

constipation. Also, the passage of a large, hard 

stool may tear the anus, leading to further pain 

and reluctance to defecate, thus greatly aggravat-

ing the problem. It is perhaps surprising that 

these tears rarely become infected and usually 

heal well.

Occasionally, constipation may be a symptom 

of serious disease. Large gallstones discharged 

into the duodenum may sometimes cause small-

bowel obstruction, usually at the ileocaecal junc-

tion, with an acute onset of symptoms, whereas 

colonic obstruction is more often insidious in 

onset. Obstruction in infants may occasionally 

be due to intussusception (the bowel folding in 

on itself). In adults, it tends to be associated with 

a benign or malignant tumour. Acute obstruc-

tion may result from DDC (see above) or volvu-

lus, i.e. twisting of the gut. Fortunately, most of 

these  organic  or  functional  conditions  are 

uncommon,  though  they  must  be  considered 

if there is no history of chronic or sporadic