Chapter 15 Alimentary system
COMMON CLINICAL PROBLEMS FROM ALIMENTARY SYSTEM DISEASE
Sign or symptom | Pathological basis |
---|---|
Dysphagia (diffi culty swallowing) | |
Heartburn (indigestion) | Oesophageal/gastric mucosal irritation, often with infl ammation and ulceration |
Abdominal pain | |
Diarrhoea | Excessive secretion or impaired absorption of fl uid within lumen of gastrointestinal tract |
Steatorrhoea (fatty stools) | Impaired absorption of fat due to reduced lipase secretion or reduced mucosal surface area for absorption |
Blood loss | |
Weight loss | |
Anaemia | Blood loss (e.g. tumour, ulcer) or impaired absorption of iron, folate or B12 due to mucosal disease |
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
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.
DISEASES OF THE ORAL MUCOSA
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.
Tumours
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.
DISEASES OF THE PHARYNX
Tumours
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
Tumours
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.
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.
OESOPHAGUS
NORMAL STRUCTURE AND FUNCTION
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.
CONGENITAL AND MECHANICAL DISORDERS
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.
INFLAMMATORY DISORDERS
Reflux oesophagitis
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:
TUMOURS
Carcinoma
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.
Adenocarcinoma
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.
STOMACH
NORMAL STRUCTURE AND FUNCTION
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.
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.
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.
INFLAMMATORY DISORDERS
Acute gastritis
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.
Chronic gastritis
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.
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.
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.
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% |
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.
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.
Gastric ulcers
The mucosal defences against acid attack consist of:
Ulceration can follow either destruction or removal of the mucus barrier, or a loss of integrity of the surface epithelium. Dissolution of the mucus layer can occur as a primary event as a consequence of duodeno-gastric reflux. The regurgitated bile from the duodenum strips off the mucus barrier and paves the way for acid attack. Acid and bile in combination damage the surface epithelial cells, increasing the permeability of the mucosa. This causes the congestion and oedema of the lamina propria seen in reflux gastritis.