Alimentary system

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Chapter 15 Alimentary system

Common clinical problems from alimentary system disease 357
Pathological basis of gastrointestinal signs and symptoms 357
MOUTH, TEETH, PHARYNX AND SALIVARY GLANDS 358
Normal structure and function 358
Congenital disorders of the mouth 358
Diseases of the teeth and gums 359
Diseases of the oral mucosa 359
Diseases of the pharynx 360
Diseases of the salivary glands 361

OESOPHAGUS 362
Normal structure and function362
Congenital and mechanical disorders362
Inflammatory disorders363
Barrett’s oesophagus364
Tumours364
STOMACH365
Normal structure and function365
Congenital disorders366
Inflammatory disorders367

Peptic ulceration369

Benign tumours and polyps372
Malignant tumours of the stomach372

INTESTINE376
Normal structure and function376
Congenital disorders378
Bacterial infections381
Viral infections383
Fungal infections383
Parasitic diseases384
Drugs and the intestine384
Chronic inflammatory disorders385

Disorders resulting from abnormal gut motility391

APPENDIX397
Appendicitis397
ANUS AND ANAL CANAL398
Normal structure and function398
Diseases of the anus and anal cana398
Commonly confused conditions and entities relating to alimentary pathology399

COMMON CLINICAL PROBLEMS FROM ALIMENTARY SYSTEM DISEASE

image

 

Pathological basis of gastrointestinal signs and symptoms—cont’d

Sign or symptom Pathological basis
Dysphagia (diffi culty swallowing)
Impaired neuromuscular function (e.g. multiple sclerosis)
Obstruction (intrinsic or extrinsic)

Heartburn (indigestion)Oesophageal/gastric mucosal irritation, often with infl ammation and ulcerationAbdominal pain

Visceral
Peritoneal
Spasm (colic) of muscular layer in gut wall
Irritation or infl ammation of peritoneum

DiarrhoeaExcessive secretion or impaired absorption of fl uid within lumen of gastrointestinal tractSteatorrhoea (fatty stools)Impaired absorption of fat due to reduced lipase secretion or reduced mucosal surface area for absorptionBlood loss

In vomit (haematemesis)
Through anus
Ruptured blood vessel in oesophagus (e.g. varices) or stomach (e.g. erosion by ulcer)
Ulceration or inflammation of colorectal mucosa, or oozing from surface of a tumour, or ruptured blood vessel (e.g. haemorrhoid, angiodysplasia)

Weight loss

Impaired food intake
Malabsorption of food
Catabolic state associated with a malignant neoplasm

AnaemiaBlood loss (e.g. tumour, ulcer) or impaired absorption of iron, folate or B12 due to mucosal disease

The alimentary system is constantly in contact with dietary contaminants, especially infective agents and environmental toxins, so it is not surprising that it is affected by many diseases. This chapter examines these diseases and, in those of major importance, attempts to relate them to the potentially pathogenic factors present in the human diet.

MOUTH, TEETH, PHARYNX AND SALIVARY GLANDS

NORMAL STRUCTURE AND FUNCTION

The mouth and teeth masticate the food prior to swallowing and digestion. At the same time digestion is initiated by the addition of salivary amylases and lipases.

The mouth is lined by stratified squamous epithelium overlying richly vascular connective tissue. The epithelium is of variable thickness, being thickest over the tongue where there are also papillary projections which account for its rougher texture. The epithelium is mostly non-keratinised, except over the lips, gums and hard palate where slight keratinisation occurs. Elsewhere pathological keratinisation (keratosis) results in the formation of white plaques on the mucosa; this is termed leukoplakia.

The teeth consist principally of dentine, which is similar to bone; it is composed of a collagen matrix mineralised by calcium phosphate (apatite) crystals. It differs from bone, however, in that its cellular constituents (odontoblasts) form a layer over the surface of the dentine, from which long tubular processes ramify through the tissue. The dentine is covered over the exposed part of the tooth (crown) by enamel, which is composed almost entirely of inorganic material arranged in stacked crystalline rods. The dentine of the root is covered by a thin layer of cementum which, as its name implies, attaches the tooth to the periodontal ‘ligament’ lining the socket. Centrally, the tooth has a connective tissue core, the pulp, which links with the narrow root canal.

The salivary glands are usually categorised as either major or minor. The major glands are the parotid, submandibular and sublingual glands; minor glands are scattered throughout the oral cavity. The parotids enclose branches of the facial nerve and a few lymph nodes. The glandular tissue comprises multiple small secretory acini lined by plump cells containing zymogen granules and surrounded by supporting myoepithelial cells. The secretion has a low protein content, hence these glandular units are referred to as serous acini. Small ducts lined by cuboidal epithelium drain the glandular lobules and unite to form the main secretory (Stensen’s) duct. The submandibular glands contain both serous and mucus-secreting cells in mixed acini; the sublingual and minor salivary glands are predominantly or entirely mucus-secreting. The main ducts of the submandibular glands (Wharton’s ducts) are lined by partly ciliated epithelium to facilitate drainage of the more viscid mucous secretion.

CONGENITAL DISORDERS OF THE MOUTH

Hare-lip and cleft palate

Hare-lip may appear as a sporadic defect of development but may also occur as an inherited condition exhibiting male sex linkage. The inherited form occurs both with and without a cleft palate. Where a cleft palate exists alone, a proportion of the cases are due to a dominant gene of low penetrance. Other cases are not genetically determined, as for example in the rubella syndrome (Ch. 5).

Hare-lip may be unilateral or bilateral; it may involve the lip only, or extend upwards and backwards to include the floor of the nose and the alveolar ridge. Cleft palate may vary considerably, from a small defect in the soft palate, which causes little disability, to a complete separation of the hard palate combined with hare-lip. With extensive lesions, there may be considerable difficulty with feeding as the child is unable to suck.

DISEASES OF THE TEETH AND GUMS

While of paramount importance to the dental student, diseases of the mouth, teeth and gums are soon evident to both patient and doctor, and frequently reflect generalised disorders. Their recognition and an understanding of the processes involved are therefore also of wider importance in clinical medicine.

Dental caries

Caries (‘tooth decay’) is the result of acid destruction of the calcified components of the teeth (Fig. 15.1). These structures are in a dynamic equilibrium between de- and re-mineralisation. When the pH falls below 5.5, de-mineralisation outstrips re-mineralisation; erosion of enamel is followed by loss of dentine. The acid is produced by bacteria, usually specific strains of Streptococcus mutans, acting mainly on refined sugar which is trapped in contact with the enamel by ‘plaque’—a mixture of adhesive sugar residues and bacteria. Thus, a lack of oral hygiene, excessive consumption of sugars and under-development of dentine contribute to the development of caries. Penetration of the dentine is followed by bacterial invasion; this can infect the pulp, causing pulpitis.

image

Fig. 15.1 Dental caries. Longitudinal sections of adjacent teeth showing characteristic erosion of enamel and dentine.

(Courtesy of Professor C J Smith, Sheffield.)

Gingivitis

Acute gingivitis (inflammation of the gums) is an uncommon infection caused by the anaerobic Borrelia vincentii and fusiform bacilli. It is a severe ulcerative disease, formerly referred to as Vincent’s infection, which can spread widely along the gum margins and deeply to destroy bone.

Chronic gingivitis, by contrast, is a very common condition which represents the response of the gum to adjacent bacterial plaque. Proliferation of anaerobic bacteria, and possibly their production of proteolytic enzymes, leads to chronic periodontitis and gradual destruction of the supporting tissues of the teeth. This results in loosening and eventual loss of teeth.

DISEASES OF THE ORAL MUCOSA

Inflammatory disorders

The oral mucous membrane is affected in a wide variety of mucocutaneous inflammatory disorders such as acute erythema multiforme, lichen planus, Behçet’s syndrome and many others. However, some conditions (discussed below) are restricted to the oral mucosa.

Herpetic stomatitis

Herpetic stomatitis is a very common manifestation of infection by herpes simplex virus. It is characterised by vesiculation and ulceration of the oral mucosa and is usually acquired during childhood. Many patients develop recurrences in later life, appearing as similar lesions on the lips (herpes labialis).

Oral candidiasis

Oral candidiasis (thrush) is caused by the yeast-like fungus Candida albicans. It appears as white plaques on the oral mucosa consisting of enmeshed fungal hyphae, which invade the epithelium, together with polymorphs and fibrin. The infection is more common in neonates, in patients receiving broad-spectrum antibiotics and in immunocompromised individuals.

Aphthous stomatitis

Aphthous stomatitis is a very common disorder in which single or, more usually, multiple small ulcers appear in the oral mucosa. They are shallow, with a grey, necrotic base and a haemorrhagic rim. Many patients suffer from recurrent crops of ulcers which heal spontaneously after several days. The aetiology is unknown but assumed to be immunological; some patients have an associated gastrointestinal disorder, such as coeliac disease or inflammatory bowel disease.

Reparative lesions

The oral mucosa is frequently subjected to minor trauma. In some individuals the reparative processes that follow prove excessive, and the surplus fibrovascular tissue appears as a polyp. Such a reparative lesion in the mouth is termed an epulis, of which ‘congenital’ and giant cell forms are recognised. There is also a similar angiomatous ‘tumour’ of pregnancy, and many of the so-called haemangiomas and fibromas of the mouth have the same histogenesis.

Oral leukoplakia and epithelial dysplasia

Leukoplakia (‘white plaque’) is a clinical term for patches of keratosis on the squamous epithelium that cannot be categorised as any other definable lesion, e.g. lichen planus or frictional keratosis. These lesions may be pre-cancerous: up to 18% of leukoplakias become oral cancer. Thus, in leukoplakia there is hyperkeratosis and hyperplasia of the squamous epithelium with, in some cases, dysplastic changes that herald the onset of malignant change. The finding of dysplasia on histological assessment is currently the best predictor of progression.

In the UK and USA, leukoplakia is associated with heavy cigarette smoking, excessive alcohol consumption and poor dental hygiene. The high incidence in India and Sri Lanka is attributed to the habit of chewing ‘quids’ made up of tobacco dust, areca nut and lime wrapped in a betel leaf.

Tumours

Cancer of the lip is more common than intra-oral cancers and occurs mainly in elderly people. It has a definite relationship to sunlight exposure; therefore, it is much more common on the lower than the upper lip. Lip cancers are usually well-differentiated squamous carcinomas which spread directly into surrounding tissues, and through lymphatics to the regional nodes.

Intra-oral cancers most frequently affect the tongue and commonly develop in areas of leukoplakia (Fig. 15.2); many oral carcinomas are associated with leukoplakia when diagnosed. The predisposing causes are therefore the same as those for leukoplakia but with the possibility that human papillomavirus (HPV) could also be implicated. ‘High-risk’ HPVs (mainly type 16 or 18) are more frequently associated with oral squamous carcinoma than low-risk HPVs. Like lip cancers, oral cancers are usually squamous carcinomas. Initially they are painless and can remain undetected, especially if situated on the posterior third of the tongue, until fixation and swelling interfere with swallowing and speech. Late presentation with nodal metastases and direct spread to vital structures explains the much poorer prognosis of cancer of the tongue compared to that of cancer of the lip.

image

Fig. 15.2 Oral cancer. Ulcerated squamous cell carcinoma (arrowed) arising from buccal mucosa.

(Courtesy of Mr P McAndrew, Rotherham.)

DISEASES OF THE PHARYNX

Pharyngitis

Viral pharyngitis

The commonest cause of pharyngitis is viral infection, but the causative virus is rarely identified. Most cases are thought to be caused by adeno- and rhinoviruses, but other viral infections, notably those directed at the respiratory tract, can be responsible. Patients with these infections either start with a pharyngitis or develop it during the illness. Thus pharyngitis is a common feature of the common cold, influenza, measles and infectious mononucleosis (glandular fever).

Streptococcal pharyngitis

Although less common than viral infections, streptococcal pharyngitis is important for its complications. In non-immune individuals a widespread skin rash (scarlet fever) develops and occasional patients will develop acute proliferative glomerulonephritis, rheumatic fever or Henoch–Schönlein purpura.

Ulcerative pharyngitis

An ulcerative pharyngitis and tonsillitis is a common complication of agranulocytosis (deficiency of polymorphs) due to a leukaemia or marrow failure. Diphtheria was formerly an important cause of an ulcerative pharyngitis, but has now been largely eradicated in many countries by immunisation.

Tonsillitis

The faucial tonsils are collections of lymphoid tissue covered by non-keratinising squamous epithelium thrown into a series of clefts; these can harbour debris and act as a nidus for infection. The tonsils are thus a frequent site for bacterial infection, producing either an acute inflammation or, more frequently, recurring chronic inflammation leading to tonsillar enlargement (through lymphoid hyperplasia) and general debility.

Tumours

The pharynx can be the site of squamous carcinoma and of intermediate or ‘transitional’ cell carcinomas, the latter exhibiting features of epithelium transitional between squamous and columnar, respiratory-type epithelium. However, most carcinomas in this site are anaplastic (undifferentiated). In addition, the tonsils may be involved by lymphomas.

Nasopharyngeal carcinoma is of interest because of the wide geographical variation in its incidence. It is an uncommon carcinoma in Caucasians, but in some parts of China (particularly Canton) the frequency is 100-fold higher than in European populations. Males are more frequently affected than females. There appears to be a link with prior infection with Epstein–Barr (EB) virus, and the susceptible Chinese show a relatively higher frequency of the histocompatibility haplotypes HLA-A2 and -Bw46.

DISEASES OF THE SALIVARY GLANDS

Sialadenitis

Acute bacterial sialadenitis (inflammation of the salivary glands) is uncommon. It arises by ascending infection from the mouth and occurs in patients with abnormal dryness of the mouth (xerostomia), either as part of a generalised dehydration or as a result of an autoimmune-induced atrophy of the salivary glands (Sjögren’s syndrome). Acute enlargement of the salivary glands is usually due to mumps virus infection.

Recurrent sialadenitis is seen in patients who have some degree of duct obstruction, hyposecretion of saliva and ascending infection. Duct obstruction can be due to a stone (calculus) or to fibrosis. Hyposecretion may be a direct consequence of duct obstruction but may also be due to the acinar atrophy resulting from sialadenitis itself. Bacterial infection leads to recurrent acute inflammation and also acts as a nidus for stone formation.

Tumours

image Pleomorphic adenoma: a benign mixed tumour
image Warthin’s tumour (adenolymphoma): a benign tumour
image Muco-epidermoid tumour: both benign and malignant forms exist
image Adenoid cystic carcinoma: has a tendency for perineural invasion

Pleomorphic adenoma

At least two-thirds of all salivary tumours are accounted for by the pleomorphic adenoma or ‘mixed tumour’, and over 80% occur in the parotid gland. As the name implies, this has a varied histological appearance and is composed of a mixture of stromal and epithelial elements (Fig. 15.3). The myxoid stroma, which is rich in proteoglycans, is thought to be produced by myoepithelial cells; thus, despite its biphasic appearance, it is a purely epithelial neoplasm. Occasionally the stroma has a cartilaginous appearance. Pleomorphic adenomas are essentially benign tumours but are prone to local recurrence if surgical removal is incomplete. The facial nerve is vulnerable during attempts at surgical removal. A very small proportion undergo malignant change and are capable of metastasising; these are termed malignant mixed tumours.

image

Fig. 15.3 Pleomorphic salivary adenoma. These benign neoplasms consist of a mixture of proliferating epithelium and mucinous connective tissue resembling cartilage surrounded by a capsule of fibrous and compressed salivary tissue.

Warthin’s tumour

Warthin’s tumour or adenolymphoma is a relatively common salivary gland tumour (5–10% of total). It has a very characteristic appearance: tall columnar epithelial cells line convoluted cystic spaces separated by a dense lymphoid stroma. The term adenolymphoma, with its connotations of lymphoid malignancy, is a misnomer; this is an entirely benign tumour.

Muco-epidermoid tumour

Muco-epidermoid tumour consists of mucus-secreting cells—cells showing squamous differentiation and intermediate cells (small cells that are probable precursors of the mucus-secreting and squamous cells). All should be considered as at least low-grade malignancy but those tumours with a greater proportion of intermediate and squamous cells compared to mucous cells have a more aggressive behaviour. Muco-epidermoid tumours comprise about 10% of all parotid tumours.

Adenoid cystic carcinoma

Adenoid cystic carcinoma is a distinctive malignancy that is relatively more common in the minor salivary glands. It is composed of small epithelial cells arranged in islands showing microcystic change. This tumour has a propensity for perineural spread and is particularly difficult to eradicate surgically.

OESOPHAGUS

NORMAL STRUCTURE AND FUNCTION

The oesophagus is a muscular tube lined mostly by squamous epithelium. It extends from the pharynx to the cardia of the stomach and is about 25cm long in the adult. At the upper end there is the cricopharyngeal sphincter; close to the lower end there is a functional sphincter whose position can be determined only by manometry. The upper sphincter contains striated muscle fibres enabling voluntary control over the initiation of swallowing, whereas the remainder of the muscular tube is composed of smooth muscle which propels the food bolus by peristalsis and is under autonomic control. Entry of food into the stomach is facilitated by relaxation of the distal sphincter. Protection of the lower oesophagus against regurgitation of gastric contents is achieved by the distal sphincter assisted by constricting muscle bands in the diaphragm, and an acute valve-like angle of entry into the stomach. The distal 1.5–2cm of the oesophagus is situated below the diaphragm and is lined by columnar mucosa of cardiac type. The squamo-columnar junction is clearly visible on endoscopy and is usually found at about 40cm (measured from the incisor teeth). Proximal extension of this junction is found in hiatus hernia or when there is columnar metaplasia.

The squamous lining of the oesophagus consists of a layer of non-keratinising squamous epithelium overlying connective tissue papillae containing blood vessels and lymphatics. A narrow layer one to two cells thick at the base of the epithelium forms the proliferative compartment from where cells migrate upwards, mature and desquamate at the surface (Fig. 15.4). These cells acquire an increasing glycogen content as they mature. Scattered argyrophil (neuroendocrine) cells and melanoblasts can also be found in the basal layer.

image

Fig. 15.4 Basal cell hyperplasia in reflux oesophagitis. image Normal cell proliferation and migration in the squamous epithelium. image In reflux oesophagitis, increased proliferation to compensate for increased cell desquamation results in basal zone hyperplasia and elongation of connective tissue papillae.

CONGENITAL AND MECHANICAL DISORDERS

Heterotopic tissue

Patches of fundic-type gastric mucosa are occasionally found above the distal sphincter and separated from the columnar lining of the distal oesophagus. These are assumed to be congenitally misplaced (heterotopic) gastric tissue rather than an acquired change; they can lead to ulceration and stricturing due to local acid/pepsin secretion.

Atresia

Atresia is a failure of embryological canalisation. It is more frequent than agenesis of the oesophagus, which is extremely rare. Atresia is usually associated with an abnormal connection (fistula) between the patent part of the oesophagus and the trachea. The affected child cannot swallow and develops an aspiration bronchopneumonia. Urgent surgical correction is required.

Diverticula

Diverticula are outpouchings of the wall of a hollow viscus. Some represent a saccular dilatation of the full thickness of the wall; others are formed by herniation of mucosa through a defect in the muscle coat. Diverticula are more common in the pharynx but can develop in the oesophagus by either traction (external forces pulling on the wall) or pulsion (forcible distension). These diverticula differ from congenital forms in lacking a muscle coat in their wall. They frequently become permanently distended with retained food and cause difficulties in swallowing (dysphagia).

Hiatus hernia

Defined as the presence of part of the stomach above the diaphragmatic orifice, hiatus hernia is the commonest mechanical disorder of the oesophagus and is found in c. 25% of people undergoing investigation for dyspepsia. The herniation of the stomach with subsequent retraction of the oesophagus is largely due to increased intra-abdominal pressure and loss of diaphragmatic muscular tone with ageing. Predisposing factors include obesity, lifting heavy loads, frequent coughing fits, tight-fitting clothes and frequent bending. The consequent incompetence of the oesophageal sphincter results in regurgitation of gastric contents leading to gastro-oesophageal reflux disease (GORD). Hiatus hernia of itself is usually asymptomatic; the condition presents with the symptoms and complications of GORD.

Achalasia

Achalasia is an uncommon condition in which the contractility of the lower oesophagus is lost and there is a failure of relaxation at the sphincter (cardiospasm).

Normal functioning of the oesophagus is dependent upon the integrity of its co-ordinated muscular activity, which in turn relies on normal neuronal transmission of peristaltic signals. Thus dysphagia may arise from fibrosis and atrophy of the smooth muscle, as occurs in progressive systemic sclerosis, or by destruction or degeneration of the intrinsic nerves. The latter can occur in neurotropic infections such as Chagas’ disease (South American trypanosomiasis), or by unknown mechanisms as in the condition of achalasia.

Achalasia results in slowing or retention of the food bolus with increasing obstruction and dilatation of the oesophagus. The cause of this condition is unknown, but there are reduced numbers of ganglion cells in the myenteric plexus, and both myelinated and unmyelinated axons of the extra-oesophageal vagus nerves show Wallerian degeneration (Ch. 6).

Oesophageal varices

Varices are localised dilatations of veins. The veins of the lower oesophagus are a potential site for porto-systemic shunting of blood when portal venous flow through the liver is impaired. Therefore, in portal hypertension (most commonly resulting from cirrhosis of the liver) the submucosal veins of the oesophagus become congested and dilate (Ch. 16). These enlarged veins elevate the mucosa and protrude into the oesophageal lumen where they are easily traumatised by the passage of food. Haemorrhage is thus a frequent complication and, because of the relatively high pressure within the vascular bed, can be torrential and life-threatening.

Mallory–Weiss tears

Two American physicians’ names are associated with rupture of the oesophageal mucosa resulting from repeated retching or vomiting. The mucosa tears in the distal oesophagus close to the gastro-oesophageal junction. This is an important cause of upper gastrointestinal haemorrhage. Bleeding usually stops after 24–48 hours and the tears heal within 10 days or so.

INFLAMMATORY DISORDERS

Oesophagitis

Acute oesophagitis

Acute oesophagitis is clinically of only minor importance. Spread of bacterial infection from the nasopharynx to involve the oesophagus is a rare occurrence. More important are viral and fungal infections in immunocompromised individuals; for example, herpes simplex and cytomegalovirus infections are occasionally encountered in patients with leukaemias, lymphomas or AIDS. Candidiasis is a more common infection which may give rise to difficulties in swallowing; it is endoscopically recognisable as white plaques with haemorrhagic margins. Candidiasis is also opportunistic in immunodeficiency states and in diabetes mellitus, but can sometimes be found in otherwise healthy individuals. A further cause of acute inflammation and ulceration is the ingestion of corrosive substances; this may be either accidental (as when children swallow chemicals from unlabelled bottles) or taken with suicidal intent.

Chronic oesophagitis

As with chronic inflammation in any site, chronic oesophagitis may be either specific or non-specific. Specific causes are rare, but involvement by tuberculosis and Crohn’s disease are recognised. Non-specific oesophagitis is very common and usually results from regurgitation of gastric contents into the lower oesophagus; this is reflux oesophagitis.

Reflux oesophagitis

Gastro-oesophageal reflux disease (GORD) is very common and is diagnosed when regurgitation causes symptoms or damages the mucosa. There is poor correlation between symptoms and oesophagitis; some patients with severe symptoms have little or no damage to the oesophageal lining whereas others with obvious inflammation on endoscopy may be asymptomatic. Clinically, GORD should be diagnosed on the basis of symptoms alone; the characteristic complaint is an awareness of acid regurgitation with central chest pain or discomfort—‘heartburn’. A defective sphincter mechanism at the cardia predisposes to this gastro-oesophageal reflux, which is therefore an invariable accompaniment of hiatus hernia. Smokers are more likely to have GORD, as are obese people.

Morphology

Exposure of the squamous mucosa to refluxed acid leads to cell injury and accelerated desquamation. The increased cell loss is compensated for by increased proliferation of the germinative cells of the epithelium (basal cell hyperplasia; see Fig. 15.4); this results in fewer mature cells occupying most of the epithelial thickness and is accompanied by elongation of the connective tissue papillae. Such elongation permits extension of the basal layer and possibly reflects an interaction between the proliferating epithelial cells and underlying mesenchyme. The epithelial injury is accompanied by a low-grade inflammatory cell response so that, in general, relatively small numbers of polymorphs (including eosinophils) and lymphocytes are seen within the epithelium and in the underlying connective tissue. Thus the response to reflux embraces both:

an epithelial reaction—basal cell hyperplasia and elongation of papillae
a conventional chronic inflammatory cell reaction.

Where reflux is severe, cell proliferation cannot keep pace with cell desquamation and ulceration occurs. These areas of ulceration can be the source of haemorrhage, and may even perforate in the most severe cases. Healing is achieved by epithelial regeneration and underlying fibrosis; subsequent shrinkage of fibrous tissue can produce a segmental narrowing (benign oesophageal stricture) in the area of healed ulceration.

Restoration of epithelial continuity is usually achieved by proliferation of squamous cells, but in some patients the lost squamous epithelium is replaced by columnar, intestinal-type epithelium, giving rise to a condition known as ‘Barrett’s oesophagus’.

BARRETT’S OESOPHAGUS

image Long-term consequence of reflux
image Metaplasia from squamous to columnar epithelium
image Increased risk of oesophageal adenocarcinoma
image Epithelial dysplasia precedes malignancy
image Regular surveillance by biopsy indicated

As a result of longstanding reflux, the lower oesophagus comes to be lined by columnar, intestinalised mucosa, an appearance referred to as Barrett’s oesophagus. Opinions vary as to whether this is due to epithelial ‘substitution’—migration of columnar epithelium from the distal 2cm or from the ducts of submucosal mucous glands—or to an effect on the differentiation of progeny cells from a common stem cell (metaplasia). The latter is held to be the main mechanism at work.

In a patient with Barrett’s oesophagus, the endoscopist sees proximal extension of pink columnar mucosa replacing the pearly white squamous epithelium. This extension is seen first as ‘tongues’ extending up from the cardia, and later as a complete ‘cylinder’ of columnar epithelium that can occupy much of the distal half of the oesophagus. Histologically, the epithelium may resemble that of the gastric cardia, but the characteristic ‘specialised’ Barrett’s metaplasia consists of columnar epithelium, with goblet cells and tall intervening mucus-producing cells both secreting intestinal-type mucins—a form of intestinal metaplasia. Metaplasias arise in response to an adverse micro-environment and can be regarded as a defensive response in which the new cell lineage has a survival advantage over the ‘native’ epithelium it has replaced. Thus, an initial change from squamous epithelium to a columnar, gastric-type mucosa is readily understood as a response to acid reflux in that it provides a more resistant mucosa. However, the change to epithelium with intestinal features cannot be explained solely as a defence response to acid. Other factors, such as bile reflux, may play a part, but it may be that patients who develop Barrett’s metaplasia have a different phenotypic response to acid injury from the outset.

Barrett’s oesophagus has become increasingly important following its recognition as a premalignant condition. Although the risk of malignancy is about 100 times higher among patients with Barrett’s oesophagus than in the general population, the absolute risk of developing adenocarcinoma remains small. Only 2–3% of affected patients die from adenocarcinoma and overall life expectancy is unchanged. Nevertheless, it is considered best practice to undertake regular surveillance once Barrett’s oesophagus has been diagnosed. If dysplasia, particularly high-grade dysplasia, is found on biopsy, then the risk of malignancy is greatly increased.

TUMOURS

Benign tumours

Benign tumours are uncommon and comprise about 5% of all neoplasms of the oesophagus; the type most frequently encountered is a leiomyoma. The behaviour of smooth muscle tumours in the alimentary tract is generally difficult to predict (see below) but those arising in the oesophagus are almost invariably benign. Other benign non-epithelial tumours—lipomas, haemangiomas and fibromas—are rare. The only benign epithelial tumour of note is squamous papilloma. Compared with squamous carcinoma (see below) these are rare lesions, certainly in terms of clinical presentation, but are of interest because they are likely to share a common pathogenesis with squamous papillomas at other sites being linked to human papillomavirus (HPV) infection.

Carcinoma

image Wide geographic variation in incidence
image Links with environmental factors
image Two main types: squamous carcinoma and adenocarcinoma
image Most adenocarcinomas arise from metaplastic columnar epithelium (Barrett’s oesophagus)

There are two main types of oesophageal carcinoma—squamous and adenocarcinoma. These differ markedly in their aetiology and epidemiology.

Squamous carcinoma

Squamous carcinoma is much more common in males than in females and shows marked geographical variation in incidence. In European countries, the age-standardised annual incidence is around 5 per 100000 population in males and 1 per 100000 in females. However, there are some well-defined high-risk areas, such as north-west France and northern Italy, where the incidence rises to 30 per 100000 in males and 2 per 100000 in females. Globally there are more striking differences. Regions with very high incidence have been identified in Iran, South Africa, Brazil and Central China. In Henan Province in China the mortality rate from carcinoma of the oesophagus exceeds 100 per 100 000 in males and 50 per 100 000 in females.

Epidemiological studies in high-incidence areas have indicated that a high dietary intake of tannic acid, in the form of strong tea or sorghum wheat, or dietary deficiencies of riboflavin, vitamin A and possibly zinc may be important, but other factors such as fungal contamination of foodstuffs, opium usage and thermal injury may also be involved. In Western countries, cigarette smoking and the drinking of alcoholic spirits are associated with a higher incidence.

A factor of current interest is the possible involvement of HPV. Some oesophageal squamous cancers contain HPV in their cells, and viruses of similar subtype can be found in intact and apparently normal oesophageal mucosa. It is therefore possible that virus integrated into the host genome can bring about oncogene activation and carcinogenesis. The involvement of papillomaviruses in the development of bovine oesophageal carcinoma is well established.

Non-specific chronic oesophagitis is common among the general population in high-incidence areas, and biopsies will frequently reveal dysplasia. The squamous epithelium shows cellular pleomorphism: there is disordered maturation with immature cells and mitotic activity appearing close to the surface. The degree of atypia can be categorised as low- or high-grade dysplasia; the latter condition will proceed to invasive carcinoma if surgical resection is not performed. As in the oropharynx, dysplasia is sometimes associated with abnormal keratosis—leukoplakia.

Adenocarcinoma

In the lower third of the oesophagus, adenocarcinomas are the predominant type. They usually develop on the basis of a Barrett’s oesophagus. The incidence has risen dramatically in recent years among white, middle-aged men in European countries and the USA; the reported annual increase in the white male population of the USA is close to 10% which exceeds that of any other malignancy in that population. Although the incidence of adenocarcinoma has increased, it is still a rare disease; in the year 2000 the numbers of new cases in Western countries varied between 1 and 5 per 100000 white males. Nevertheless this incidence approaches, and in some areas exceeds, that of squamous carcinoma of the oesophagus.

Carcinoma of the oesophagus, either squamous or adenocarcinoma, usually commences as an ulcer, but spreads to become annular and constricting so that the patient develops dysphagia (difficulty in swallowing) (Fig. 15.5). However, by the time most patients present, direct spread outside the oesophagus has occurred and the surgical resection rate is only about 40%. Resectability and ultimate survival can be improved by pre-operative chemo-irradiation. Those patients who cannot be surgically treated may undergo chemo- or radiotherapy alone, or receive palliative laser therapy. Unfortunately, a substantial proportion of patients are simply intubated to facilitate adequate nutrition. The long-term outlook is therefore very poor; only 5% survive for 5 years. Most patients die from local disease and bronchopneumonia exacerbated by malnutrition. Unlike many forms of cancer, metastases are uncommon at autopsy.

image

Fig. 15.5 Carcinoma of the oesophagus. The oesophagus has been opened to reveal an ulcerated tumour partly obstructing its lumen. Blood loss from the ulcerated surface can lead to anaemia, and the partial obstruction causes dysphagia.

Other tumours

Other rare malignant tumours arising in the oesophagus include malignant melanoma (from the melanocytes that are present in very small numbers in normal mucosa), small cell anaplastic carcinoma from neuroendocrine precursors, mixed adenosquamous carcinomas and sarcomas.

STOMACH

NORMAL STRUCTURE AND FUNCTION

The stomach acts essentially as a ‘mixing’ reservoir for food during acid–pepsin digestion. Hydrochloric acid and pepsin are, however, only two of many products of the gastric mucosa.

Histologically, the stomach can be divided into three regions—the cardia, body and antrum. The surface of the gastric mucosa and its pits (foveolae) are lined throughout by columnar mucus-secreting epithelium. The mucus secreted by these cells, together with contributions from the antral mucous glands, forms a viscid gel covering the mucosa—the gastric mucus barrier (Fig. 15.6). Bicarbonate and sodium ions, also secreted by surface epithelial cells, diffuse into the unstirred gel and buffer the hydrogen ions entering from the luminal aspect. A pH gradient is thus established, ranging from 1 or 2 at the luminal surface of the barrier, to neutrality at the plasma membrane of the epithelium. The glandular component varies from region to region.

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Fig. 15.6 The gastric mucus barrier. The surface epithelial cells (supplemented by foveolar and glandular mucous cells) secrete viscid mucus which forms an unstirred layer between the epithelium and the gastric lumen. The surface cells also secrete sodium and bicarbonate ions into the mucus gel and a pH gradient is established. This constitutes the major defence against acid attack.

The cardiac (or junctional) mucosa is a narrow zone immediately below the termination of the squamous-lined oesophagus; it comprises simple tubular or cystic glands, lined by mucus-secreting cells, in which endocrine cells are scattered.

Body mucosa lines the proximal two-thirds of the stomach and consists of tightly packed tubular glands, the upper parts of which are lined by parietal cells (acid producing) and the lower parts by chief cells (pepsinogen) (Fig. 15.7A). In addition to acid, the parietal cells secrete intrinsic factor, essential for vitamin B12 absorption. Other cells present in body mucosa are mucous neck cells and endocrine cells. The neck cells are found at the bases of the gastric pits, i.e. at the junction between foveolar lining cells and glandular cells, and contain the stem cells of the mucosa together with some immature foveolar cells. The majority of the endocrine cells are so-called enterochromaffin-like (ECL) cells which are readily identifiable by silver staining (argyrophil) techniques. These cells modulate parietal cell activity by releasing histamine in response to stimulatory hormones such as gastrin.

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Fig. 15.7 Structure of the gastric mucosa. image Body (corpus) mucosa where the tubular glands contain specialised secretory cells. The ‘neck’ cells represent the proliferative compartment of the gastric pit from where the majority of cells migrate upwards to replenish exfoliated surface cells, and a minority move downwards to replace glandular cells. image Antral mucosa, predominantly composed of mucus-secreting cells but with scattered endocrine cells.

Antral (or pyloric) mucosa occupies a roughly triangular region proximal to the pylorus, with its base about one-third of the distance along the lesser curvature and its apex a few centimetres from the pylorus on the greater curve. The antral glands are more branched, tortuous and less tightly packed than those in the body (Fig. 15.7B). The glands are lined by mucus-secreting cells with faintly granular cytoplasm and basal nuclei, together with endocrine cells. There may be occasional parietal cells. The endocrine cells of the antrum produce several hormones: G cells secreting gastrin are the most numerous, but others include D cells (which secrete somatostatin), EC cells (5-hydroxytryptamine, 5-HT), P cells (bombesin) and S cells (secretin).

CONGENITAL DISORDERS

Congenital abnormalities, apart from hypertrophic pyloric stenosis, are rare. They include accessory structures lined by gastric mucosa, which are referred to as ‘cysts’ when saccular and not communicating with the gastric lumen, ‘duplications’ if tubular and non-communicating, and ‘diverticula’ if they communicate.

Diaphragmatic hernia

Maldevelopment of the diaphragm can lead to defects though which the stomach, together with parts of the intestine and the spleen, herniate into the left thoracic cavity. Usually only part of the stomach is dislocated into the thorax, but after birth it may become expanded by swallowed air and can rapidly compress the lungs and, very rarely, cause death from respiratory failure.

Pyloric stenosis

An abnormal hypertrophy of the circular muscle coat at the pylorus can cause outflow obstruction from the stomach. The condition, found in approximately 4 per 1000 live births, usually presents 2–3 weeks after birth with projectile vomiting. It is four to five times more common in males than in females. The primary abnormality appears to lie in the enteric nervous system at this site; the interstitial cells of Cajal (see p. 378) are either absent or abnormal.

INFLAMMATORY DISORDERS

image Acute gastritis is commonly due to chemical injury (e.g. alcohol, drugs)
image Commonest form of chronic gastritis results from Helicobacter pylori infection
image Chronic gastritis can also result from an autoimmune process, often causing vitamin B12 deficiency
image Chemical (reactive) gastritis is caused by biliary regurgitation or drug-induced damage

Inflammation of the stomach, as with other organs, is usually considered as either acute (often described as ‘haemorrhagic’ or ‘erosive’) or chronic gastritis. One form of chronic gastritis, formerly designated type A, has long been recognised as an autoimmune disorder, but this type is uncommon. The major form of chronic gastritis (type B) is the result of infection with the bacterium Helicobacter pylori. Finally, longstanding bile reflux gives rise to a third major category—a ‘chemical’ type gastritis—which could therefore be termed ‘type C’.

Acute gastritis

Acute gastritis is almost invariably an acute response to an irritant ‘chemical’ injury by drugs or alcohol. The principal drugs involved are non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, but many others have been implicated. These agents cause a prompt exfoliation of surface epithelial cells and diminished secretion of mucus such that the protective barrier against acid attack (see below) may be compromised. Many of their effects are probably mediated by an inhibition of prostaglandin synthesis.

Depending on the severity of the injury, the mucosal response varies from vasodilatation and oedema of the lamina propria, to erosion and haemorrhage. An erosion is an area of partial loss of the mucosa, as opposed to an ulcer where the full thickness, i.e. below the muscularis mucosae, is lost. The erosions in acute gastritis are frequently multiple and the resultant haemorrhage can be severe and life-threatening. Fortunately, the lesions are transient and heal rapidly by regeneration, so that erosions may well have disappeared 24–48 hours after the bleeding episode.

An acute neutrophilic gastritis (i.e. one in which polymorph infiltration is a dominant feature) is characteristic of the initial response to Helicobacter pylori infection. Acute Helicobacter gastritis is a transient phase which in the majority of individuals is subclinical and over the course of 3–4 weeks gives way to chronic gastritis. In a minority of individuals the infection is spontaneously eradicated and the inflammatory response resolves. The pathological features of acute bacterial gastritis are summarised in Table 15.1.

Table 15.1Pathological features of Helicobacter-associated gastritis

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Chronic gastritis

Autoimmune chronic gastritis

A few patients with chronic gastritis are found to have antibodies in their serum directed against gastric parietal cells and intrinsic factor binding sites. These patients exhibit varying degrees of hypochlorhydria (they are often achlorhydric), and have a macrocytic anaemia resulting from vitamin B12 deficiency; this association of autoimmune gastritis with macrocytic anaemia is called pernicious anaemia.

Histologically, the body of the stomach is maximally affected: there is marked loss of parietal cells (glandular atrophy) and replacement fibrosis of the lamina propria, together with an infiltrate of lymphocytes and plasma cells. In addition, the surface and pit-lining epithelium may show intestinal metaplasia (IM), a change common to all forms of longstanding chronic gastritis. In this form of metaplasia, the neutral, mucin-secreting cells characteristic of the stomach are replaced by goblet cells containing acidic glycoproteins typical of the intestine. In well-developed cases there may also be absorptive cells and Paneth cells. Intestinal metaplasia is generally regarded as a premalignant condition; however, the risk is low and cancer develops in only a very small proportion of people with IM. Another type of metaplasia in the stomach could be more important in cancer development: parietal gland atrophy is accompanied by a multifocal proliferation of mucous glands—usually referred to as pyloric gland metaplasia—and this is more strongly associated with gastric cancer than IM. However, neither IM nor pyloric gland metaplasia is sufficiently closely related to cancer development to be useful for identifying ‘high-risk’ patients.

Helicobacter-associated chronic gastritis

The commonest cause of chronic gastritis is bacterial infection by Helicobacter pylori. This is a Gram-negative organism that inhabits a peculiarly protected niche closely applied to the surface epithelium beneath the mucous barrier where the pH approaches neutrality. Besides taking advantage of this acid-protected niche, the organism has its own intrinsic acid buffering mechanism using its urease and ammonia production to neutralise hydrogen ions gaining access to its periplasmic space. The organism binds to the surface cells and, depending on its virulence, exerts cytopathic effects that lead to accelerated cell exfoliation and a polymorph and chronic inflammatory cell response (Fig. 15.8). H. pylori is found in over 90% of biopsies showing active chronic (type B) gastritis but is very uncommon in the autoimmune type. The gastritis resolves after successful eradication of infection with antibiotics. Interestingly, the organism is found only on gastric epithelium and does not colonise duodenal (or any other intestinal) epithelium.

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Fig. 15.8 Gastritis resulting from Helicobacter pylori infection. image At low magnification, the biopsy reveals an influx of chronic inflammatory cells into the mucosa and lymphoid follicle formation. image A section specially stained to reveal numerous minute curved Helicobacter adherent to the mucosal surface.

The neutrophil polymorph response provoked by H. pylori is mediated partly by leukotactic complement components liberated through activation of the alternative pathway (Ch. 9), but principally by bacteria-induced production of interleukin-8 by epithelial cells, macrophages and endothelial cells. Polymorphs subsequently release proteases, reactive oxygen metabolites (ROMs) and reactive nitrogen species into the mucosa. ROM production by leukocytes is enhanced by cytokines, such as tumour necrosis factor-alpha (TNF-alpha), and their cytopathic effects may be responsible for the glandular loss (atrophy) that characterises longstanding chronic gastritis. Anti-H. pylori IgA, IgG and IgM antibodies are produced locally by plasma cells in the lamina propria as part of a Th2-mediated response (Ch. 9); these antibodies have a role in the prevention of bacterial adhesion and in opsonisation, but fail to eliminate the infection.

Histologically, Helicobacter-associated gastritis affects the entire stomach mucosa but to a variable degree. The majority of patients have diffuse involvement of the antrum and body with gradual glandular atrophy, replacement fibrosis and intestinal metaplasia. The loss of parietal cells leads to hypochlorhydria and a reduction in the secreted signals that modulate the growth and differentiation of progenitor cells in the gastric mucosa; this could explain the link between atrophy and metaplasia. Patients with widespread gastritis have an increased risk of gastric ulcer and carcinoma compared with uninfected individuals. A second main pattern is where the antrum is markedly inflamed but with little involvement of body mucosa. These individuals have increased acid output rendering the body mucosa more hostile to H. pylori colonisation. Patients with this antrum-predominant gastritis have a greater risk of duodenal ulcer. Overall, however, only 10–15% of individuals infected with H. pylori develop peptic ulcer disease, and the risk of gastric cancer is about 1–3%. The histological features of acute and chronic gastritis are summarised in Table 15.1.

Chemical (reflux) gastritis

The presence of regurgitated bile and alkaline duodenal juice in the stomach provokes epithelial cell loss, compensatory hyperplasia of the proliferative compartment in the gastric foveolae, and vasodilatation and oedema of the lamina propria; this is reflux gastritis. In ‘normal’ people there is little or no regurgitation of duodenal contents into the stomach. Reflux gastritis is seen in the post-operative stomach following operations that destroy or bypass the pylorus, as a result of secondary motility disturbances in patients with gallstones and after cholecystectomy, and in some patients who appear to have a disturbance of antro-duodenal motility or co-ordination. Unoperated patients with bile reflux appear to have a failure in pyloric competence resulting from a disturbance in pyloro-antral motor function; this may be either a primary disturbance, or a defective response to hormones, such as cholecystokinin and secretin, which normally increase pyloric tone during duodenal acidification. The ensuing reflux gastritis stimulates production of gastrin by the antral mucosa; this may also block the effects of cholecystokinin and secretin on the pyloric muscles.

Reflux gastritis may present with bilious vomiting or less severe dyspeptic symptoms; repeated damage to the mucosa may lead to the development of a gastric ulcer.

A similar histological picture to that found with bile reflux can result from long-term usage of NSAIDs; the common denominator is repeated chemical injury. The various types of chronic gastritis are compared in Table 15.2.

Table 15.2Types of chronic gastritis

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Other forms of gastritis

Less common forms of chronic gastritis have been distinguished from the three major types discussed above.

In lymphocytic gastritis the main histological feature is the presence of numerous mature lymphocytes within the surface epithelium. This form is occasionally seen in patients who have peculiarly heaped-up erosions running along prominent rugal folds. Most patients are histologically H. pylori-negative at the time of diagnosis but most show serological evidence of infection. Some cases are related to villous atrophy and altered small intestinal function.

Eosinophilic gastritis is characterised by oedema and a large number of eosinophils in the inflammatory cell infiltrate. It is thought to be an allergic response to a dietary antigen to which the patient has become sensitised, or in some countries to parasitic infestation.

Granulomatous gastritis is a rare form of gastritis in which epithelioid cell granulomas are found. Such granulomas can be part of Crohn’s disease (p. 385) or sarcoidosis, but after exclusion of these causes there remains an isolated granulomatous gastritis of unknown aetiology.

PEPTIC ULCERATION

Peptic ulceration is a breach in the mucosa lining the alimentary tract as a result of acid and pepsin attack. Gastric and duodenal ulcers differ in their epidemiology, incidence and pathogenesis (Table 15.3). They arise as either acute or chronic ulcers.

Table 15.3 Comparison of the epidemiology, incidence and aetiology of gastric and duodenal ulcers

Feature Gastric ulcer Duodenal ulcer
Incidence (relative) 1 3
Age distribution Increases with age Increases up to 35 years of age
Social class More common in low socio-economic classes Even distribution
Blood group A O
Acid levels Normal or low Elevated or normal
Helicobacter gastritis About 70% 95–100%

image Major sites: first part of duodenum, junction of antral and body mucosa in stomach, distal oesophagus and gastro-enterostomy stoma
image Main aetiological factors: hyperacidity, Helicobacter gastritis, duodeno-gastric reflux, NSAIDs, smoking and genetic factors
image Ulcers may be acute or chronic
image Complications include haemorrhage, penetration of adjacent organs, perforation, anaemia, obstruction due to fibrous strictures, and malignancy

Acute ulcers

Acute peptic ulcers develop:

as part of an acute gastritis
as a complication of a severe stress response
as a result of extreme hyperacidity.

Deeper extension of the erosions in acute gastritis resulting from NSAIDs or acute alcohol overdosage can produce frank ulcers. Acute ulcers occur also in a heterogeneous group of conditions where stress seems to be the common denominator. For example, ulcers may be found following severe burns (Curling’s ulcer), major trauma or cerebrovascular accidents. Such ulcers probably arise as a consequence of mucosal ischaemia, which lowers the mucosal resistance to acid. Extreme hyperacidity, as seen for example in patients with gastrin-secreting tumours (Zollinger–Ellison syndrome), can lead to multiple acute ulcers in the antrum, the duodenum and even the jejunum.

Chronic ulcers

Chronic peptic ulcers (Fig. 15.9) seem to occur most frequently at mucosal junctions. Thus gastric ulcers are often found where antral meets body-type mucosa on the lesser curvature; duodenal ulcers are found in the proximal duodenum close to the pylorus; oesophageal peptic ulcers are found in the squamous epithelium just above the cardio-oesophageal junction; and stromal ulcers—those occurring following construction of a gastro-enterostomy linking stomach and jejunum—are found in the jejunal mucosa immediately adjacent to the gastric mucosa of the stromal margin. This suggests that ulceration is most likely to occur where acid and pepsin first come into contact with a susceptible mucosa.

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Fig. 15.9 Chronic gastric ulcer. Histological section through the ulcer revealing a deep breach of the main muscle layers and haemorrhage around an artery (arrowed) in the ulcer base. The patient presented with a profuse haematemesis (vomiting blood) and underwent emergency partial gastrectomy.

Pathogenesis

For many years peptic ulceration has been attributed to excessive acid production. However, there are many problems with this hypothesis. People with gastric ulcers frequently have normal or even subnormal acid production, and over one-half of duodenal ulcer patients do not have hyperacidity. Conversely, many people who are hypersecretors of acid do not get ulcers. Furthermore, while most ulcers respond initially to anti-acid treatment there are frequent relapses. It has therefore become increasingly apparent that mucosal defence against acid attack is of considerable importance (Fig. 15.10). Failure of the mucosal defence mechanisms means that ulcers can result from normal or even decreased quantities of acid.

image

Fig. 15.10 Peptic ulceration. ‘An ulcer represents the adverse outcome of a conflict between aggressive forces in the stomach or duodenum and the defence mechanisms.’ (Sir Francis Avery-Jones) image Normal. Acid/pepsin attack is balanced by the mucus barrier and other defence mechanisms. image Increased attack. Hyperacidity (as in the Zollinger–Ellison syndrome) or NSAIDs may bring about the ulceration of ‘normal’ mucosa in the stomach and duodenum. image Weakened mucosal defence. This is the major factor in peptic ulceration. Chronic inflammation in the gastric and duodenal mucosa resulting from Helicobacter pylori infection can lead to ulceration in the presence of normal or even reduced levels of acid. Duodenal inflammation results from infection of patches of acid-induced gastric metaplasia in the first part of the duodenum.

Gastric ulcers

The pH of the gastric juice under fasting conditions is extremely acidic (between 1 and 2) so that any unprotected gastric mucosa would rapidly undergo auto-digestion.

The mucosal defences against acid attack consist of:

a mucus–bicarbonate barrier
the surface epithelium.

The mucus barrier is the more important of the two lines of defence. The pit-lining and surface epithelial cells of the stomach secrete viscid neutral glycoproteins which form a layer of unstirred mucus on the surface. The mucus itself has acid-resistant properties, but its protective power is greatly enhanced by the establishment of a buffering gradient within the layer brought about by bicarbonate ions.

The surface epithelium constitutes a second line of defence; for its proper functioning it requires integrity of both the apical plasma membrane as a barrier to ion transfer, and cellular metabolic functions, including the production of bicarbonate. These functions are dependent upon an adequate mucosal blood supply.

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