Category Archives: Gastroenterology

Inflammatory bowel disease

Two major forms of non-specific inflammatory bowel disease are recognized: Crohn’s disease, which can affect any part of the gastrointestinal tract, and ulcerative colitis, which affects only the large bowel. There is overlap between these two conditions in their clinical features, and histological and radiological abnormalities;
in 10% of cases of colitis a definitive diagnosis of either ulcerative colitis or Crohn’s disease is not possible. Currently, it is necessary to distinguish between these two conditions because of certain differences in their management. However, it is possible that these conditions represent two aspects of the same disease. The incidence of Crohn’s disease varies from country to country but is aproximately 5-6 per 100000 with a prevalence of  5O 60 per 100000. The incidence of ulcerative colitis is 5-10 per 100000 per year with a prevalence of 80-120 per 100 000.

EPIDEMIOlOGY AND AETIOLOGY

The aetiology is unknown, but the racial differences and geographical clustering suggest both genetic and environmental causes. A cluster of patients with Crohn’s disease has been found in a Cotswold village in England. both  conditions have a worldwide distribution but are more common in the Western World. The incidence is lower in the non-White races. Jews are more prone o inflammatory bowel disease than non-Iews: the Ashkenazi jew have a higher risk than the Sephardic Jews. 1 Familia}. Both conditions are more common amongst relatives of patients than in the general population. There is a high rate of disease concordance in mono-zygotic twins.
2 Genetic, There are no HLA markers but HLA-B27 is increased in patients with inflammatory bowel disease and ankylosing spondylitis.
3 Smoking. Patients with Crohn’s disease are more likely to be tobacco smokers, and there is an increased risk ofulcerative colitis amongst non-smokers or ex-smokers.
4 infecive agent. In Crohn’s disease the most attractive hypothesis is that of a transmissible agent. No bac-terium, virus or parasite has been definitely identified; recently the measles virus has been implicated.
(a) Mycobacterium. In cattle and sheep, Iohne’s disease, which is a chronic inflammatory disorder of the distal ileum, is caused by M. paratuberculosis.
A mycobacterium has been isolated from Crohn’s disease tissue, but current evidence is against this being an aetiological agent. Granulomas are characteristic of Crohn’s disease, but are also seen in TB and sarcoidosis suggesting a common pathogenetic link, although none has been found.

(b) Cell wall deficient organisms, L-forms, plasmids may be the transmissible agent but this theory  lacks any evidence.
(c) Viruses have been reported in tissue from ulcerative colitis and Crohn’s disease patients, but there are no compelling data.
5 Multifocal gastrointestinal infarction due to granulomatous angiitis has been suggested as a primary event in Crohn’s disease.
6 Serum antineutrophil cytoplasmic antibody (ANCA) is increased in ulcerative colitis, but not Crohn’s disease; it is distinct from the ANCA seen in Wegener’s granulomatosis. 7 Many immunological abnormalities have been described in inflammatory bowel disease. It is unclear whether they are the primary or secondary event in the pathogenesis. A suggested mechanism is that a specific or generalized luminal antigen can cause stimulation of immune (antigen specific) or inflammatory (antigen non-specific) responses. It is possible that these responses are abnormal or exaggerated in inflammatory bowel disease. Activation of T lymphocytes, tissue macrophages, eosinophils, mast cells, neutrophils and fibroblasts produce a wide variety of cytokines (e.g. interleukin IL-1, IL-6, TNF), eicosanoids (e.g. prostaglandins, thromboxane, LTB4), cell adhesion markers (e.g. E-selectins and endothelial cell leucocyte adhesion molecule (ELAM)) and free oxygen radicals, all of which can lead to tissue damage.

PATHOLOGY

Crohn’s disease is a chronic inflammatory condition that may affect any part of the gastrointestinal tract from the mouth to the anus but has a particular tendency to affect the terminal ileum. The disease can involve one small area of the gut such as the terminal ileum, or multiple areas with relatively normal bowel in between (‘skip lesions’). It may also be extensive, involving the whole of the colon
and/or small bowel. Ulcerative colitis can affect the rectum alone
(proctitis), can extend proximally to involve the sigmoid and descending colon (,left-sided colitis’), or may involve the whole colon (‘total colitis’). In a few of these patients there is also inflammation of the distal terminal ileum (‘backwash ileitis’).

Macroscopic changes

In Crohn’s disease the involved bowel is usually thickened and narrowed. There are deep ulcers and fissures in the mucosa, producing a cobblestone appearance. Fistulas and abscesses may be seen. An early sign is aphthoid ulceration that can be seen endoscopically. In ulcerative colitis the mucosa looks reddened, inflamed and bleeds easily. In severe disease there is extensive ulceration, with the adjacent mucosa appearing as inflammatory polyps. In fulminant disease most of the mucosa is lost, leaving a few islands of oedematousmucosa (mucosal islands) and toxic dilatation occurs. On healing, the mucosa can return to normal, although there is usually some residual glandular distortion.

Microscopic changes

In Crohn’s disease the inflammation extends through all layers of the bowel, whereas in ulcerative colitis a superficial inflammation is seen. In Crohn’s disease there is an increase in chronic inflammatory cells and lymphoid hyperplasia, and in 50- 60% of patients granulomas are present. These granulomas are non-caseating epithelioid cell aggregates with Langhans’ giant cells.
In ulcerative colitis the mucosa shows a chronic inflammatory cell infiltrate in the lamina propria. Crypt  bscesses and goblet cell depletion are also seen. The differentiation between these two diseases is made not only on the basis of clinical and radiological data but also on the histological differences seen in the rectal and colonic mucosa obtained by biopsy.

CLINICAL FEATURES

Crohn’s disease

This can present at any age; it is uncommon before the age of 10 years and has a peak incidence between 20 and 40 years. A late peak affecting mainly the colon has been reported in women aged over 60 years. Both sexes are equally affected.
The major symptoms are of diarrhoea, abdominal pain and weight loss. Constitutional symptoms of malaise, lethargy, anorexia, nausea, vomiting and low-grade fever may be present. Despite the recurrent nature of this condition, many patients remain well and have an almost normal life-style. However, patients with extensive disease may have frequent recurrences necessitating multiple hospital admissions.
The clinical features are very variable and depend partly on the region of the bowel that is affected. The disease may present insidiously or acutely. The abdominal pain may be colicky, suggesting obstruction but it usually has no special characteristics and sometimes in colonic disease only minimal discomfort is present. Diarrhoea is present in 80% of all cases and in colonic disease usually contains blood, making it difficult to differentiate from ulcerative colitis. Steatorrhoea can be present in small bowel disease. Some patients (15%) present with only anorexia, weight loss and general ill-health, with an absence of any other gastrointestinal symptoms.

Histological differences between Crohn's disease and ulcerative colitis.

Histological differences between Crohn’s disease
and ulcerative colitis.

bowel disease. Some patients (15%) present with only anorexia, weight loss and general ill-health, with an absence of any other gastrointestinal symptoms. Crohn’s disease may present as an emergency with acute right iliac fossa pain mimicking appendicitis. If laparotomy is undertaken, an oedema to us, reddened terminal ileum is found. There are many other causes of an acute ileitis, e.g. infections such as Yersinia. Crohn’s diseaseis the cause of approximately 10% of acute ileitis.

EXAMINATION. Physical signs are few, apart from loss  of weight and general ill-health. Aphthous ulceration of the mouth is often seen. Abdominal examination is often normal, although tenderness and a right iliac fossa mass are occasionally found. This mass is due either to inflamed loops of bowel that are matted together or to an abscess. A careful examination of the anus should always be made to look for oedematous anal tags, fissures or perianal abscesses. These abnormalities are particularly common (80%) in colonic involvement. Other extra-gastrointestinal features of inflammatory bowel disease should be looked for, e.g. erythema nodosum, arthritis, iritis . Sigmoidoscopy should always be performed in a patient with Crohn’s disease. With small bowel involvement the rectum may appear normal, but a biopsy must be taken as non-specific histological changes may sometimes be found in the mucosa. Even with extensive colonic Crohn’s disease the rectum may be spared and be relatively normal, but patchy involvement with an oedematous haemorrhagic mucosa can be present.

Ulcerative colitis

This also occurs at any age, but most frequently between 20 and 40 years with women affected more than men. The major symptom in ulcerative colitis is diarrhoea with blood and mucus, sometimes accompanied by lower abdominal discomfort. General features include malaise, lethargy and anorexia. Aphthous ulceration is seen. The disease can be mild, moderate or severe, and runs a course of remissions and exacerbations. Ten per cent of patients have persistent chronic symptoms, although some patients may have only a single attack. When the disease is confined to the rectum, blood mixed with the stool, urgency and tenesmus are common. In this group, there are normally very few constitutional symptoms but patients are nevertheless greatly inconvenienced by the frequency of defecation. In an acute attack patients have bloody diarrhoea, passing 10-20 liquid stools per day. Diarrhoea also occurs at night, with urgency and incontinence that is severely disabling for the patient. Occasionally blood and mucus alone are passed.

The definition of a severe attack is given. The patient may be very ill and needs careful monitoring in hospital with prompt treatment to avoid the development of complications, such as septicaemia, toxic dilatation and perforation.
EXAMINATION. In general there are no specific signs in ulcerative colitis. The abdomen may be slightly distended or tender to palpation. The anus is usually normal. Rectal examination will show the presence of blood. Sigmoidoscopy is always abnormal and shows an inflamed, bleeding, friable mucosa. A biopsy should be taken for histological diagnosis.

Markers of a severe attack of ulcerative colitis.

Markers of a severe attack of ulcerative colitis.

Extra-gastrointestinal manifestations These occur with both diseases and some are related to the intestinal disease activity Patients with Crohn’s colitis have more extra-gastrointestinal complications than those with small bowel lesions alone.

INVESTIGATION

There may be a palpable mass and a small bowel followthrough will detect most lesions. Ultrasound and CT will show bowel wall thickening and the involvement of lymph nodes which is common with lymphoma. Biopsies, to determine histological type, are helpful to decide treatment.

TREATMENT

Treatment is often with resection, radiotherapy and chemotherapy. The 5-year survival rate for T-cell lymphomas is 25%, but is better for B-cell lymphomas, varying from 50 to 75%, depending on the grade of lymphoma.

Carcinoid tumours

These originate from the enterochromaffin cells (APUD cells, see p. 204) of the intestine. They make up 10% of all small-bowel neoplasms, the commonest sites being in the appendix, terminal ileum and the rectum. It is often difficult to be certain histologically whether a particular tumour is benign or malignant. Clinically most carcinoid tumours are asymptomatic until metastases are present. Ten per cent of carcinoid tumours in the appendix present as acute appendicitis, the inflammation being secondary to obstruction. Surgery is sometimes necessary for localized turnours. CARCINOID SYNDROME. This syndrome occurs in only5% of patients with carcinoid tumours and only when there are liver metastases. Patients complain of spontaneous or induced bluish-red flushing, predominantly on the face and neck. This can lead to permanent changes with telangiectasis. Gastrointestinal symptoms consist of abdominal pain and recurrent watery diarrhoea. Cardiac abnormalities are found in 50% of patients and consist of tricuspid incompetence or pulmonary stenosis.
Examination of the abdomen reveals hepatomegaly.
BIOCHEMICAL ABNORMALITIES. The turn ours secrete a variety of biologically active amines and peptides, including serotonin (5-hydroxytryptamine; 5HT), bradykinin, histamine and tachykinins as well as prostaglandins. The diarrhoea and cardiac complications are probably caused by 5HT itself but the cutaneous flushing is thought to be produced by one of the kinins, such as bradykinin, which is known to cause vasodilatation, bronchospasm and increased intestinal motility.

DIAGNOSIS

Ultrasound examination confirms the presence of secondary deposits and the major metabolite of 5HT, 5-hydroxyindoleacetic acid (5HIAA), is found in high concentration in the urine.

TREATMENT

Octreotide is an octapeptide somatostatin analogue that has been shown to inhibit the release of many gut hormones. It alleviates the flushing and diarrhoea and can control a carcinoid crisis. It is given subcutaneously in doses up to 200 IJ..gthree times daily.
Octreotide sometimes inhibits tumour growth and, since its introduction, other therapy is usually unnecessary. Interferon and other chemotherapeutic regimens occasionally reduce tumour growth, but have not been shown to increase survival. Most patients survive for 5- 10 years after diagnosis.

Whipple’s disease

This is a rare disease usually affecting males. It presents with steatorrhoea and abdominal pain along with systemic symptoms of fever and weight loss. Peripheral lymph adenopathy, arthritis and involvement of the heart, lung and brain may occur. Histologically, the villi are stunted and contain diagnostic periodic acid-Schiff (p AS )-positive macro phages. On electron microscopy, bacilli can be seen ‘within’ the macrophages. The organism has been identified by the polymerase chain reaction and is similar to actinomycetes and has been given the name.

Tropheryma whippeii

A dramatic improvement occurs with antibiotic therapy, which should include an antibiotic that crosses the blood-brain barrier, e.g. chloramphenicol.

RADIATION ENTERITIS

Radiation of more than 50 Gy will damage the intestine. The ileum and rectum are the areas most often involved, as pelvic irradiation is the common cause. There may be diarrhoea and abdominal pain at the time of the irradiation. These symptoms usually improve within 6 weeks after completion of therapy. Chronic radiation enteritis is diagnosed if symptoms persist for 3 months or more. The prevalence is more than 15%, although many more patients suffer from an increased bowel frequency.

Rectal damage produces a radiation proctitis with diarrhoea, with or without blood and tenesmus. Treatment is symptomatic; local steroids sometimes help. Radiation enteritis produces muscle fibre atrophy, ulcerative changes due to ischaemia, and obstruction due to strictures produced by radiation-induced fibrosis. The symptoms are often that of obstruction, which is usually partial but eventually may be complete. Malabsorption due to mucosal damage as well as bacterial overgrowth in dilated segments can occur. Treatment is symptomatic although often unsuccessful in chronic enteritis. Surgery should be avoided if at all possible, being reserved for life-threatening situations such as complete obstruction
or occasionally perforation.

Parasite infestation

Giardia lamblia  not only produces diarrhoea but can produce malabsorption with steatorrhoea. Minor changes are seen in the jejunal mucosa and the organism can be found in the jejunal fluid or mucosa. Cryptosporidiosis  can also produce malabsorption. Other causes of malabsorption
DRUGS that bind bile salts, e.g. cholestyramine, and some antibiotics, e.g. neomycin, produce steatorrhoea. THYROTOXICOSIS. Diarrhoea, rarely with steatorrhoea, occurs in thyrotoxicosis owing to increased gastric emptying and motility. Steatorrhoea occurs in the Zollinger- Ellison syndrome .
INTESTINAL LYMPHANGIECTASIA produces diarrhoea and rarely steatorrhoea.
LYMPHOMA that has infiltrated the small bowel mucosa.

IN DIABETES MELLITUS, diarrhoea, malabsorption and steatorrhoea occur in some patients, sometimes due to bacterial overgrowth from stasis.
HYPOGAMMAGLOBULINAEMIA, which is seen in a number of conditions including lymphoid nodular hyperplasia, causes steatorrhoea owing either to an abnormal jejunal mucosa or to secondary infestation with G. lamblia.

MISCELLANEOUS INTESTINAL

DISEASES

Protei n-Iosi n9 enteropathy

Protein-losing enteropathy is seen in many gastrointestinal and systemic conditions. Increased protein loss across an abnormal mucosa causes hypoalbuminaemia. Causes include inflammatory or ulcerative lesions, e.g. Crohn’s disease, tumours, Menetrier’s disease, coeliac disease and lymphatic disorders, e.g. lymphangiectasia. Usually it forms a minor part of the generalized disorder, but occasionally hepatic synthesis of albumin cannot compensate for the hypoalbuminaemia, and the peripheral oedema produced may dominate the clinical picture. The investigations are described on p. 207 and treatment is that of the underlying disorder.
Meckel’s diverticulum. This is the commonest congenital abnormality of the gastrointestinal tract, affecting 2-3% of the population. The diverticulum projects from the wall of the ileum approximately 60 ern from the ileocaecal valve. It is usually symptomless, but 50% contain gastric mucosa that secretes hydrochloric acid. Peptic ulcers can occur and may bleed  or perforate. Acute inflammation of the diverticulum also occurs and is indistinguishable clinically from acute appendicitis. Obstruction from an associated band rarely occurs. Treatment is surgical removal.

Tu bercu losis

Tuberculosis (TB) can affect the intestine as well as the peritoneum. Intestinal TB is due to reactivation of primary disease caused by Mycobacterium tuberculosis. Bovine TB occurs in areas where milk is unpasteurized and is very rare in the UK. The ileocaecal area is most commonly affected, but the colon, and rarely other parts of the gastrointestinal tract, can also be involved. TB is being seen more frequently in patients with HIV infection.

CLINICAL FEATURES

These are chiefly diarrhoea and abdominal pain with generalized systemic manifestations, including anorexia and weight loss. Intestinal obstruction may develop. On examination, a mass may be palpable and 50% have X-ray evidence of pulmonary TB; this is animportant aid to the diagnosis.

DIAGNOSIS

In the western hemisphere TB must be differentiated from Crohn’s disease and should always be considered as a possible diagnosis in Asian immigrants. A caecal carcinoma can present with similar symptoms. An ultrasound of the abdomen may show mesenteric thickening and lymph node enlargement. Histological verification and culture of tissue is highly desirable, but it is not always possible to obtain bacteriological confirmation and treatment should be started if there is a high degree of suspicion. Specimens can be obtained by colonoscopy but laparotomy is required in some cases.

TREATMENT

Drug treatment is similar to pulmonary TB, i.e. rifampicin, isoniazid and pyrazinamide , but treatment should last 1 year. Amyloid In systemic amyloidosis there is usually a diffuse involvement that may affect any part of the gastrointestinal tract. Occasionally amyloid deposits occur as polypoid lesions. The symptoms depend on the site of involvement; amyloidosis in the small intestine gives rise to diarrhoea. Connective-tissue disorders
SYSTEMIC SCLEROSIS  most commonly affects the oesophagus (see p. 184), although the small bowel and colon are often found to be involved if the appropriate radiological studies are performed. Frequently there are no symptoms of this involvement, but diarrhoea and steatorrhoea can occur. This is usually dueto bacterial overgrowth of the small bowel as a result of reduced motility, dilatation and the presence of diverticula. In rheumatoid arthritis (see p. 387) and systemic lupus erythematosus, gastrointestinal symptoms may occur, but rarely predominate.

Chronic intestinal ischaemia

This is due to atheromatous occlusion of mesenteric vessels in the elderly, although such occlusion often does not produce clinical effects because of the collateral circulation. The characteristic symptom is abdominal pain occurring after food. This may be followed by acute mesenteric vascular occlusion . Loud bruits may be heard but, as these are heard in normal subjects, they are of doubtful significance. The diagnosis is made using angiography. The term ‘coeliac axis compression syndrome’ has been used in young patients with chronic abdominal pain, bruits and minor angiographic changes. Despite its plausible title, it is not an organic syndrome. Its suggested existence results from the false correlation of pain and bruits.

Eosinophilic gastroenteritis

This is a condition of unknown aetiology in which there may be eosinophilic infiltration and oedema of any part of the gastrointestinal mucosa. It usually involves the gastric antrum and proximal small intestine either as a localized lesion (eosinophilic granuloma) or diffusely with sheets of eosinophils seen in the serosal and submucosallayers. An association with asthma, eczema and urticaria has been described.
The condition may occur at any age, but mainly in the third decade. Males are affected twice as often as females. The clinical presentation depends on the site of involvement. Abdominal pain, nausea and vomiting occur. An increased number of eosinophils in the blood is present in only 20% of patients. Radiology or endoscopy will demonstrate the lesion. Steroids are used for the widespread infiltration, particularly if peripheral eosinophilia is present. In some adults the condition appears to be allergic allergic gastroenteritis) and is associated with peripheral eosinophilia and high levels of blood and tissue IgE. Intestinal lymphangiectasia Dilatation of the lymphatics may be primary or secondary to lymphatic obstruction, such as that occurring in malignancy or constnctive pericarditis. In the rare primary form it may be detected incidentally as dilated lacteals on a jejunal biopsy or it can produce steatorrhoea of varying degrees. Hypoproteinaemia with ankle oedema is the other main feature. Serum immunoglobulin levels are reduced with low circulating lymphocytes. Treatment is with a low-fat diet.

Abetalipoproteinaemia

In this rare condition, there is failure of apo BlOO synthesis in the liver and apo B48 in the intestinal cell, so that chylomicrons are not formed. This leads to fat accumulation in the intestinal cells, giving a characteristic histological appearance of the jejunal mucosa. Clinical features include acanthocytosis (spiky red cells due to membrane abnormalities), a form of retinitis pigmentosa, and mental and neurological abnormalities. The latter can be prevented by vitamin E injections. Gastrointestinal problems in patients with H IV infection

TUMOURS OF THE SMALL

INTESTINE

The small intestine is relatively resistant to the development of neoplasia and only 3-6% of all gastrointestinal tumours and fewer than 1% of all malignant lesions occur in the small bowel. The reasons for the rarity of tumours are unknown. Explanations include the fluidity and relative sterility of small bowel contents and the rapid transit time, reducing the time of exposure to potential carcinogens. It is also possible that the high population of lymphoid tissue and secretion of IgA in the small intestine protects against malignancy.

Benign

Adenomas, leiomyomas or lipomas are rarely found and are usually asymptomatic and picked up incidentally. In familial adenomatous polyposis the upper gut, particularly the duodenum, is affected in one-third of patients. Peutz-Iegher syndrome consists of mucocutaneous pigmentation (circumoral, hands and feet) and gastrointestinal polyps and has a Mendelian dominant inheritance.
The brown buccal pigment is characteristic of this condition. The polyps, which are hamartomas, can occur anywhere in the gastrointestinal tract but are most frequent in the small bowel. They may bleed or cause intussusception. They virtually never become malignant. Treatment is by individual polypectomy. Multiple polypectomies may have to be performed, but bowel resection should be avoided.

Malignant

Adenocarcinoma of the small intestine is rare and found most frequently in the duodenum in the periampullary region and in the jejunum. Lymphomas are most frequently found in the ileum. These are of the non-Hodgkin’s type and must be distinguished from peripheral or nodal lymphoma involving the gut secondarily.
In developed countries, the commonest type of lymphoma is the B-cell type arising from MALT. These lymphomas tend to be annular or polypoid masses in the distal or terminal ileum, whilst most T-cell lymphomas are ulcerated plaques or strictures in the proximal small bowel.
A tumour similar to Burkitt’s lymphoma also occurs and commonly affects the terminal ileum of children in North Africa and the Middle East. Adenocarcinoma is the commonest malignancy of the small intestine accounting for up to 50% of primary tumours. Carcinoid turn ours form the next major group with lymphoma and small muscle tumours making up the remainder.

Predisposing factors

COELIAC DISEASE. There is an increased incidence of lymphoma of the T-cell type and adenocarcinoma of the small bowel in coeliac disease. There is also an increase in other malignancies both of the gastrointestinal tract and elsewhere. The reason for the local development of malignancy is unknown. It is now accepted that coeliac disease is a premalignant condition, but there is no association with a poor response to a gluten- free diet or to the chronicity of symptoms. There is some evidence that treatment of coeliac disease with a gluten-free diet protects against the development of either lymphoma or carcinoma.

CROHN’S DISEASE. There is a small increase in the incidenceof adenocarcinoma of the small bowel in Crohn’s disease.
IMMUNOPROLIFERATIVE SMALL INTESTINAL DISEASE

(IPSID) is a B-Iymphocyte disorder in which there is proliferation of plasma cells in the lamina propria of the upper small bowel. These cells produce truncatedmonoclonal heavy chains, but lack associated light chains. The a-chains are found in the gut mucosa on immunofluorescence and these can also be detected in the serum. IPSID occurs usually in countries surrounding the Mediterranean, but it has also been found in other developing countries in South America and the Far East. Recently the condition has been documented in the developed world. IPSID predominantly affects people in lower socio-economic groups in areas with poor hygiene and a high incidence of bacterial and parasitic infection of the gut. IPSID presents itself as a malabsorptive syndrome associated with diffuse lymphoid infiltration of the small bowel and neighbouring lymph nodes. This then progresses in some cases to an immunoblastic lymphoma.

CLINICAL FEATURES

Patients present with abdominal pain, diarrhoea, anorexia, weight loss and symptoms of anaemia.

Dermatitis herpetiformis

This is an uncommon blistering subepidermal eruption of the skin associated with a gluten-sensitive enteropathy. Rarely there may be gross malabsorption, but usually the jejunal morphological abnormalities are not as severe as in coeliac disease. The inheritance and immunological abnormalities are the same as for coeliac disease. The skin condition responds to dapsone but both the gut and the skin will improve on a gluten-free diet.

Incidence of malignancy In various gastrointestinal disorders, compared to familial adenomatous polyposis.

Incidence of malignancy In various gastrointestinal disorders, compared to familial adenomatous polyposis.

Tropical sprue

This is a condition presenting with malabsorption that occurs in residents or visitors to a tropical area where the disease is endemic. Malabsorption of a mild degree, sometimes following an enteric infection, is quite common and is usually asymptomatic. The term tropical sprue is reserved for severe malabsorption (of two or more substances) that is usually accompanied by diarrhoea and malnutrition. Tropical sprue is endemic in most of Asia, some Caribbean islands, Puerto Rico and parts of South America. Epidemics occur, lasting up to 2 years, and in some areas repeated epidemics occur at varying intervals of up to 10 years.

AETIOLOGY

The aetiology is unknown, but is likely to be infective because the disease occurs in epidemics and patients improve on antibiotics. A number of agents have been suggested but none has been shown to be unequivocally responsible. Different agents could be involved in different parts of the world. An overgrowth of coliforms that produce an enterotoxin has been reported.

CLINICAL FEATURES

These vary in intensity and consist of diarrhoea, anorexia, abdominal distension and weight loss. The onset is sometimes acute and occurs either a few days or many years after being in the tropics. Epidemics. can break out in villages, affecting thousands of people at the same time. The onset can also be insidious, with chronic diarrhoea and evidence of nutritional deficiency. The clinical features of tropical sprue vary in different parts of the world, particularly as different criteria are used for diagnosis.

DIAGNOSIS

ACUTE INFECTIVE causes of diarrhoea must be excluded (see p. 228), particularly Giardia, which can produce a syndrome very similar to tropical sprue.

MALABSORPTION should be demonstrated, particularly fat and vitamin BI2 malabsorption.
THE JEJUNAL MUCOSA is abnormal, showing some villous atrophy (partial villous atrophy). In most cases the lesion is less severe than that found in coeliac disease, although it affects the whole small bowel. Mild changes can be seen in asymptomatic individuals in the tropics, so jejunal mucosal changes must be interpreted carefully.

TREATMENT

Many patients improve when they leave the sprue area and take folic acid (5 mg daily). Most patients also require an antibiotic (usually tetracycline 1 g daily) to ensure a complete recovery; it may be necessary to give this for up to 6 months. The severely ill patient requires resuscitation with fluids and electrolytes for dehydration; any nutritional deficiencies should be corrected. Vitamin Bl2 (1000 /-Lg) is also given to all acute cases.

PROGNOSIS

The prognosis is excellent. Mortality is usually associated with water and electrolyte depletion, particularly in epidemics. Bacterial overgrowth The upper part of the small intestine is almost sterile, containing only a few organisms derived from the mouth. Gastric acid kills most organisms and intestinal motility keeps the jejunum empty. The normal terminal ileum contains faecal-type organisms, mainly Escherichia coli and anaerobes. Bacterial overgrowth is normally only found associated with a structural abnormality of the small intestine, although it can occur alone in the elderly. Aspiration of the upper jejunum will reveal the presence of E. coli and/or Bacteroides, both in concentrations greater than 106/rnl as part of a mixed flora. These bacteria are capable of deconjugating and dehydroxylating bile salts, so that uncnjugated and dehydroxylated bile salts can be detected in aspirates by chromatography. Steatorrhoea (see p. 202) occurs as a
result of conjugated bile salt deficiency.
The bacteria are able to metabolize vitamin BI2 and interfere with its binding to intrinsic factor, thereby leading to vitamin BI2 deficiency; this can be demonstrated using the Schilling test. Conversely some bacteria produce folic acid.
Bacterial overgrowth has only minimal effects on other substances absorbed from the small intestine. The clinical features are chiefly diarrhoea, steatorrhoea and vitamin BI2 deficiency, although this is not so severe as to produce a neurological deficit.
Although bacterial overgrowth may be responsible for the presenting symptoms, it must be remembered that many of the symptoms may be due to the underlying small bowel pathology.

TREATMENT

If possible, the underlying lesion should be corrected, e.g. a stricture should be resected. With multiple diverticula, grossly dilated bowel, or in Crohn’s disease, this may not be possible and rotating courses of antibiotics are necessary, such as metronidazole and tetracycline, or ciprofloxacin.

Intestinal resection

Intestinal resection is usually well tolerated, but massive resection is followed by the short-gut syndrome. The effects of resection depend on the extent and the areas involved.
EXTENT. Because the gut is long, a 30-50% resection can usually be tolerated without undue problems. lleal resection The ileum has specific receptors for the absorption of bile salts and vitamin B12, so that relatively small resections will lead to malabsorption of these substances. Removal of the ileocaecal valve increases the incidence of diarrhoea. In ileal resection:
• Bile salts and fatty acids enter the colon and interfere with water and electrolyte absorption, causing diarrhoea.
• Increased bile salt synthesis can compensate for loss of approximately one-third of the bile salts in the faeces. Greater loss than this results in decreased micellar formation and steatorrhoea, and lithogenic bile and gallstone formation.
• Increased oxalate absorption is caused by the presence of bile salts in the colon. This gives rise to renal oxalate stones.
• There is a low serum vitamin B12 and macrocytosis.

 INVESTIGA TION. This includes a small bowel followthrough, measurement of vitamin Bw bile salt and occasionally fat absorption.
MANAGEMENT. Many patients require vitamin B12 replacement and some need a low-fat diet if there is steatorrhoea. If diarrhoea is a problem, cholestyramine or aluminium hydroxide mixture to bind bile salts sometimes helps.

The effects of resection of distal small bowel.

The effects of resection of distal small bowel.

Jejunal resection

Here the ileum can take over jejunal absorptive function. Jejunal resection may lead to gastric hypersecretion with high gastrin levels; the exact mechanism of this is unclear. Intestinal adaptation takes place, with an increase in the absorption per unit length of bowel. Massive resection (short-gut syndrome) This can occur following resection in Crohn’s disease, mesenteric occlusion or trauma. Diarrhoea with severe loss of water and electrolytes occurs together with malnutrition. Parenteral nutrition (sometimes long term) is necessary. With intestinal adaptation most will eventually recover, although they continue to have diarrhoea and little functional reserve should another gastrointestinal problem occur.

COELIAC DISEASE (GLUTENSENSITIVE ENTEROPATHY)

Coeliac disease is a condition in which there is an abnormal jejunal mucosa that improves morphologically when the patient is treated with a gluten-free diet and relapses when gluten is reintroduced. Gluten is contained in the cereals wheat, rye, barley and possibly oats. Dermatitis herpetiformis is a skin disorder that is associated with a gluten-sensitive enteropathy.

INCIDENCE

Coeliac disease is common in Europe, with an incidence in the UK of approximately 1 in 2000. In Ireland, however, this is 1 in 300. It occurs throughout the world but is rare in the Black African.

INHERITANCE

There is an increased incidence of coeliac disease within families but the exact mode of inheritance is unknown; 10-15% of first-degree relatives will have the condition, although it may be asymptomatic. Over 90% of patients have the haplotype HLA-A1, B8, DR3, DR7, DQW2 as compared to 20-30% of the general population. However, the fact that not all patients have this haplotype and that as many as 30% of identical twins are discordant for the condition suggests an additional factor such as a Bcell antigen, immunoglobulin heavy-chain allotype or an environmental factor.

AETIOLOGY

Gluten is a high-molecular-weight, heterogeneous compound that can be fractionated to produce a, {3, ‘Y and w gliadin peptides. a-Gliadin is injurious to the small intestinal mucosa although there is some disagreement about the toxicity of other peptides. The exact mechanism of how the damage is produced is still not understood. There are many immunological abnormalities that revert to normal on treatment. An immunogenetic mechanism may be possible in view of the increased incidence of a particular HLA haplotype. An environmental factor, such as a viral infection, may playa role in view of the amino acid sequence homology between gliadin and adenovirus 12.

Disorders of the small intestine causing malabsorption. acid sequence homology between gliadin and adenovirus 12.

Disorders of the small intestine causing malabsorption. acid sequence homology between gliadin and adenovirus

PATHOLOGY

The mucosa of the proximal small bowel is predominantly affected, the mucosal damage decreasing in severity towards the ileum as the gluten is digested into smaller non-toxic fragments. Under the dissecting microscope there is an absence of villi, making the mucosal surface flat. Histological examination shows that the crypts are elongated, with chronic inflammatory cells in the lamina propria. The lesion is described as subtotal villous atrophy, although true atrophy of the mucosa is not present because the crypt hyperplasia compensates for villous atrophy and the total mucosal thickness is normal. The surface cells become cuboidal. There is an increase in the number of lELs (per 100 epithelial cells) which show an increased expression of the ‘Y/6 TCR, instead of the al{3 receptor, and this appears to be specific to coeliac disease. In the lamina propria there is an increase in lymphocytes and plasma cells.

CLINICAL FEATURES

Coeliac disease can present at any age. In infancy it appears after weaning on to gluten-containing foods. The peak incidence in adults is in the third and fourth decades, with a female preponderance. The symptoms are very variable and often non-specific with tiredness and malaise. Common gastrointestinal symptoms include diarrhoea or steatorrhoea, abdominal discomfort or pain and weight loss.
Mouth ulcers and angular stomatitis are frequent and can be intermittent. Rare complications include tetany, osteomalacia, neurological symptoms such as paraesthesia, muscle weakness or peripheral neuropathy, or gross malnutrition with peripheral oedema. There is an increased incidence of atopy and autoimmune disease, including thyroid disease and insulindependent diabetes. Other associated diseases include inflammatory bowel disease, chronic liver disease and fibrosing allergic alveoli tis. Physical signs are usually few and non-specific and are related to anaemia and malnutrition.

INVESTIGATION

JEJUNAL BIOPSY. The mucosal appearance of a jejunal biopsy specimen is diagnostic and this investigation should always be performed in suspected cases. Other causes of a flat mucosa in adults are rare and are shown. If the biopsy is performed endoscopically, a dye can be injected on to the duodenal mucosa to accentuate the smoothness of the mucosa (positive dye test) before the biopsy is taken.
HAEMATOLOGY. A mild or moderate anaemia is present in 50% of cases. Folate deficiency is almost invariably present in coeliac disease, giving rise in most instances to a high MCV. Vitamin B12 deficiency is rare but iron deficiency due to malabsorption of iron and increased loss of desquamated cells is common. A blood film may therefore show microcytes and macrocytes as well as hypersegmented polymorphonuclear leucocytes and Howell-Jolly bodies (due to splenic atrophy).
ANTIRETICULIN ANTIBODIES and endomysial antibodies (IgA) are found in the serum of the majority of cases.
ABSORPTION TESTS are often abnormal but are seldom performed.
SMALL BOWEL FOLLOW-THROUGH may show dilatation of the small bowel with a change in fold pattern; folds become thicker and in the severer forms total effacement is seen.
OTHER BIOCHEMICAL ABNORMALITIES are seen in the severely ill patient, e.g. hypoalbuminaemia.

Small bowel appearances on dissecting microscopy (OM) and histology. (a) Normal mucosa (OM). (b) Coeliac disease (OM); note flattened mucosa. (c) Normal mucosa histology (xl0). (d) Coeliac disease histology showing subtotal villous atrophy.

Small bowel appearances on dissecting microscopy (OM) and histology. (a) Normal mucosa (OM). (b) Coeliac disease (OM);
note flattened mucosa. (c) Normal mucosa histology (xl0).
(d) Coeliac disease histology showing subtotal villous atrophy.

TREATMENT AND MANAGEMENT

A gluten-free diet usually produces a rapid clinical and orphological improvement. Replacement haematinics are given initially to replace body stores. The usual cause for failure to respond to the diet is poor compliance. A gluten challenge, i.e. reintroduction of gluten with evidence of jejunal morphological change, confirms the daignosis. In the straightforw ard cases this is not necessary, although transient gluten intolerance has been described in early childhood. Many patients do not keep to a strict diet but nevertheless maintain good health. The long-term effects of this low gluten intake are uncertain.

COMPLICATIONS

A few patients do not improve on a strict diet unresponsive ‘coeliac disease’). Often no cause for this is found, but intestinal lymphoma, ulcerative jejunitis or carcinoma are sometimes responsible. The incidence of small intestinal T-cell lymphoma  is increased in coeliac disease. Carcinoma of the small bowel and oesophagus as well as extra-gastrointestinal cancers are also seen.  shows the incidence of malignancy compared to the incidence in other gastrointestinal disorders. Malignancy seems to be unrelated to the duration of the disease but the incidence may be reduced by a gluten-free diet.

Other tests

[14C)GLYCOCHOLIC ACID BREATH TEST 

This is performed to look for bacterial overgrowth. The patient is given 14C-labelled bile salts by mouth. Bacteria deconjugate the bile salts, releasing [14C)glycine, which is metabolized and appears in the breath as l4C02. This radioactivity in the breath can easily be measured. An early rise indicates either bacterial overgrowth in the upper small intestine or rapid transit to the colon where, of course, bacteria are normally present.
HYDROGEN BREATH TEST. This is frequently used as a screening test to detect bacterial overgrowth. Oral lactulose or glucose is metabolized by bacteria with the production of hydrogen. An early rise in the breath hydrogen will indicate bacterial breakdown in the small intestine. Rapid transit of the lactulose to the large intestine will also produce a rise in breath hydrogen. As bacteria are present in the oral cavity, the mouth should be rinsed out with an antiseptic mouthwash prior to the test being performed. This test is simple to perform and it does not involve radioisotopes. However, interpretation is often difficult.
DIRECT INTUBATION. Aspiration of intestinal juices is another method by which bacterial contamination can be detected. Bacterial counts are performed on aerobic and anaerobic cultures. Chromatography of bile salts can also be performed on the aspirate to detect evidence of deconjugation by bacteria.
PANCREATIC TESTS diagnosis of steatorrhoea.
OTHER BLOOD TESTS. Serum immunoglobulins are measured to exclude immune deficiencies. Hormones, e.g. VIP, are measured in high-volume secretory diarrhoea.
TEST FOR PROTEIN-LOSING ENTEROPATHY. Intravenous radioactive chromium chloride (SICrCI3) is used to label circulating albumin. In excess gastrointestinal protein loss, the faeces will contain radioactivity. This test is rarely required unless a low serum albumin is a major clinical feature.
BILE SALT LOSS. This can be demonstrated by giving oral 23-selena H,25-homotaurocholate (Se HeAT, a synthetic taurine conjugate) and measuring the retention of the bile acid by whole body counting at 7 days.
INTESTINAL PERMEABILITY TESTS. These tests can be used for the detection of small bowel disease but are not in general use. They are based on the fact that the abnormal intestinal mucosa is permeable to large molecules such as lactulose and cellobiose. An oral load of these sugars is given and the sugars are then measured in the urine. A radiolabelled sodium-EDT A solution has been used in a similar way and is said to be a more accurate investigation.

MALABSORPTION

In many small bowel diseases, malabsorption of specific substances occurs, but these deficiencies do not dominate the clinical picture. An example is Crohn’s disease, in which malabsorption of vitamin Bl2 can be demonstrated, but this is not usually a problem and diarrhoea and general ill-health are the major features.
Steatorrhoea – malabsorption of fat – is discussed The major disorders of the small intestine that cause malabsorption are shown.

The [14Clglycocholic acid breath test. The apparatus is shown on the left. The graph shows the amount of 14C02 expired in the breath after an oral dose of [14C]glycocholic acid in a normal subject and in a patient with diverticula of the small intestine.

The [14Clglycocholic acid breath test. The apparatus is shown on the left. The graph shows the amount of 14C02 expired in the breath after an oral dose of [14C]glycocholic acid in a normal subject and in a patient with diverticula of the small intestine.

Peptide production

The hormone-producing cells of the gut are scattered diffusely throughout its length and also occur in the pancreas. The cells that synthesize these hormones are derived from neural ectoderm and are known as APUD (amine recursor uptake and decarboxylation) cells. Many of these hormones have very similar structures. Although they can be detected by radioimmunoassay in the circulation, their action is often local.

Gastrointestinal peptides.

Gastrointestinal peptides.

 shows some gut hormones and their possible physiological actions. Many are also found in other tissues, particularly the brain. A number do not act as true hormones but act as neurotransmitters or have local effects on adjacent cells only (paracrine effects).
The exact physiological role of these peptides is still being evaluated. Their importance clinically is that they may be secreted in excess, particularly in endocrine turn ours of the pancreas . Growth factors, like transforming growth factor e, are also produced by intestinal cells.

Gut motility

The contractile patterns of small intestinal muscles are primarily determined by integrated neural circuits within the gut wall-the enteric nervous system. The central nervous system and gut hormones also have a modulatory role on motility. During fasting, a distally migrating sequence of motor events termed the migrating motor  complex (MMC) occurs in a cyclical fashion. The MMC consists of a period of motor quiescence (phase I) followed by a period of irregular contractile activity (phase II), culminating in a short (5-10 min) burst of regular phasic contractions (phase III). Each MMC cycle lasts for approximately 90 min. In the duodenum, phase III is associated with increased gastric, pancreatic and biliary secretions. The role of the MMC is unclear, but the strong phase III contractions propel secretions, residual food and desquamated cells towards the colon, acting as an ‘intestinal housekeeper’.
After a meal, the MMC pattern is disrupted and replaced by irregular contractions. This seemingly chaotic fed pattern lasts typically for 2-5 hours, depending on the size and nutrient content of the meal. The irregular contractions of the fed pattern have a mixing function, moving intraluminal contents to and fro, aiding the digestive process.

PRESENTING FEATURES OF SMALL BOWEL

DISEASE

Regardless of the cause, the common presenting features of small bowel disease are:

DIARRHOEA. This is a common feature of small bowel disease but approximately 10-20% of patients will have no diarrhoea or any other gastrointestinal symptoms. Steatorrhoea is occasionally present.
ABDOMINAL PAIN AND DISCOMFORT. Abdominal distension can cause discomfort and flatulence. The pain has no specific character or periodicity and is not usually severe.
WEIGHT LOSS. Weight loss is due to the anorexia that invariably accompanies small bowel disease. Although malabsorption occurs, the amount is small relative to intake.
NUTRITIONAL DEFICIENCIES. Deficiencies of iron, vitamin B]2>folate or all of these, leading to anaemia, are the only common deficiencies. Occasionally malabsorption of other vitamins or minerals occurs, causing bruising (vitamin K deficiency), tetany (calcium deficiency), osteomalacia (vitamin D deficiency), or stomatitis, sore tongue and aphthous ulceration (multiple vitamin deficiencies). Ankle oedema may be seen and is partly nutritional and partly due to intestinal loss of albumin.

PHYSICAL SIGNS OF SMALL BOWEL DISEASE

These are few and non-specific. If present they are associated with anaemia and the nutritional deficiencies described above.
Abdominal examination is often normal, but sometimes distension and, rarely, hepatomegaly or an abdominal mass are found. In the severely ill patient gross malnutrition with muscle wasting is seen. A neuropathy, not always due to vitamin B12deficiency, can be present.

INVESTIGATION OF SMALL BOWEL DISEASE

Blood tests

FULL BLOOD COUNT and film. Anaemia can be microcytic (low mean corpuscular volume [MCV]) or macrocytic (high MCV). The blood film may also show other abnormal cells, e.g. Howell-Jolly bodies, which are seen in splenic atrophy associated with coeliac disease.
SERUM IRON. If the MCV is low, serum iron and total iron-binding capacity or serum ferritin are determined.
SERUM VITAMIN BI2/FOLATE. If the MCV is high, serum vitamin B12,serum and red cell folate are determined. However, with mixed deficiencies, the MCV may be normal. The red cell folate is a good indicator of the presence of small bowel disease. It is frequently low in both coeliac disease and Crohn’s disease which are the two commonest causes of small bowel disease in developed countries.
SERUM ALBUMIN gives some indication of the nutritional status.
Low SERUM CALCIUM and raised alkaline phosphatase may indicate the presence of osteomalacia.
AUTOANTIBODIES. In countries with a high incidence of coeliac disease, measurement in the serum of antireticulin and/or endomysial antibodies are a useful adjunct for the diagnosis of coeliac disease. If the clinical suspicion of malabsorption is high, the structure of the small bowel should be studied next.

Small bowel anatomy

SMALL BOWEL FOLLOW-THROUGH . This detects gross anatomical defects such as diverticula, strictures and Crohn’s disease. Dilatation of the folds and a changed fold pattern may suggest malabsorption but, as these are not specific findings, the diagnosis should not be based on these alone. Gross dilatation is seen in pseudo-obstruction.
JEJUNAL BIOPSY (Practical box 4.4). This is used to assess the microanatomy of the small bowel. Biopsies can be obtained via an endoscope passed into the duodenum either with a Crosby-Kugler capsule inserted retrogradely up the endoscope or with a grab biopsy using large forceps. Alternatively, specimens can be obtained by swallowing a Crosby-Kugler capsule. With either technique, an adequate piece of tissue, well orientated, is necessary for correct evaluation initially under a dissecting microscope. The histological appearances will be described in the sections on individual diseases.
A smear of the jejunal juice or a mucosal impression can also be made and is helpful in the diagnosis of Giardia lamblia .

Tests of absorption

These are only required in complicated cases.

Flow diagram for investigation of patients with suspected small bowel disease. MCV; mean corpuscular volume.

Flow diagram for investigation of patients with
suspected small bowel disease. MCV; mean corpuscular volume.

FATMALABSORPTIONTh. e confirmation of the presence of steatorrhoea is occasionally necessary. The fat content of stools is measured using a 3-day collection of faeces with the patient on a diet containing 100 g of fat daily. Normal faecal fat excretion is less than 17 mmol (6 g) per day. To avoid faecal collections, fat absorption can also be measured using breath analysis. Following oral administration of a radiolabelled fat load, the amount of “C02 in the expired breath gives an indication of the amount of fat malabsorption. Comparison between a labelled triglyceride ([“Cltriolein) and a labelled fatty acid ([3Hloleic acid) is used to diagnose pancreatic disease, when fatty acid absorption will be normal.

D-XYLOSE TOLERANCE TEST. Xylose is a sugar which is absorbed from the proximal small intestine. The urinary xylose excretion and the blood xylose level following an oral dose reflect its absorption. This test tends to produce many false-positives and although still used in some centres it should be phased out.
LACTOSE TOLERANCE TEST. This involves the oral ingestion of 50 g of lactose and the measurement of blood glucose. The test is oflittle use in adults as lactose intolerance is not a clinical problem since these patients avoid milk by choice. There is a high incidence of lactase deficiency in many parts of the world, e.g. the Mediterranean countries, and parts of Africa and Asia. It should be remembered that a glass of milk only contains approximately 11 g of lactose. A glucose tolerance test should not be performed, as it is influenced by many factors other than absorption.

SCHILLING TEST. This is performed to look for vitamin Bl2 malabsorption. It is described in detail . In gastrointestinal disease it is used to detect:
• Pernicious anaemia
• Ileal disease (when oral vitamin Bl2 is given with intrinsic factor)
• Bacterial overgrowth (measurement of vitamin Bl2 plus intrinsic factor absorption is repeated after antibiotics)

Jejunal biopsy.

Jejunal biopsy.

The small intestine

STRUCTURE

The small intestine extends from the duodenum to the ileum. Its surface area is enormously increased by mucosal folds. In addition, the mucosa has numerous finger-like projections called villi and the surface area is further increased by microvilli . Each villus consists of a core containing blood vessels, lacteals (lymphatics) and cells, e.g. plasma cells and lymphocytes, and is covered by epithelial columnar cells that are absorptive. Opening into the lumen between the villi are the crypts of Lieberkiihn. The epithelial cells are formed at the bottom of these crypts and migrate to the tops of the villi, from where they are shed. This process takes 3-4 days. On its luminal side the epithelial cell has a brush border of microvilli that is covered by the glycocalyx. The lamina propria contains plasma cells, lymphocytes, macrophages, eosinophils and mast cells. Scattered throughout the gut are peptidesecreting cells.
Most of the blood supply to the small intestine is via branches of the superior mesenteric artery. The terminal branches are end arteries, i.e. there are no local anastomotic connections.
Histochemically there are three types of nerves in the gut:
• Cholinergic parasympathetic (with muscarinic or nicotinic receptors)

• Adrenergic sympathetic (with both a and f3 receptors)

• Non-cholinergic, non-adrenergic. The transmittershere are thought to be either cyclic nucleotides and A TP (the purinergic system) or intestinal hormones, e.g. vasoactive intestinal peptide (VIP) (peptidergic system) or nitric oxide which is now thought to act as a neurotransmitter.

he structure of the small intestine.

he structure of the small intestine.

FUNCTION

The small intestine is concerned with the digestion and absorption of nutrients, salt and water. It produces many enzymes and hormones in order to carry out these processes. Nutrients can be absorbed throughout the small intestine with the exception of vitamin BJ2 and bile salts, which have specific receptors in the terminal ileum. The small intestine also has local defence mechanisms to prevent antigens from entering the body.

Functions of the small intestine.

Functions of the small intestine.

General principles of absorption

SIMPLE DIFFUSION. This process requires no energyand takes place if there is a concentration gradient from he intestinal lumen (high concentration) to the bloodstream (low concentration).
ACTIVE TRANSPORT. This requires energy and can work against a concentration gradient. A carrier protein is required and the process is sodium dependent. For example, glucose enters the enterocyte on the luminal side via a sodium-dependent carrier molecule and leaves on the serosal side via a sodium-independent carrier that is found in the basolateral membrane. A gradient is maintained across the membrane by an energy-dependent sodium pump (Na”, K+ATPase) that keeps the intracellular sodium concentration low.
FACILITATED DIFFUSION. This is an energy-independent carrier-mediated transport system that allows a faster absorption rate than simple diffusion, e.g. fructose absorption.

Absorption in the small intestine

CARBOHYDRATE. Dietary carbohydrate consists mainly of starch with some sucrose and a small amount of lactose. Starch is a polysaccharide made up of numerous glucose units. Its hydrolysis begins in the mouth by salivary amylase. The majority of hydrolysis takes place in the upper intestinal lumen by pancreatic amylase. This hydrolysis is limited by the fact that amylases have no specificity for some glucose/glucose branching links.

The small intestine

The small intestine

These breakdown products, together with sucrose and lactose, are hydrolysed on the brush border membrane by their appropriate oligo- and di-saccharidases to form the monosaccharides glucose, galactose and fructose. These monosaccharides are transported into the cells, largely by sodium-dependent active transport systems.
PROTEIN. Dietary and endogenous proteins (desquamated cells, intestinal secretions) are mainly digested by pancreatic enzymes prior to absorption. These proteolytic enzymes are secreted as proenzymes and transformed to active enzymes in the lumen. The presence of protein in the lumen stimulates the release of enterokinase, which activates trypsinogen to trypsin, and this in turn activates the other proenzymes, chymotrypsin and elastase. These enzymes break down protein into oligopeptides. Some diand tri-peptides are absorbed intact by a carrier-mediated process, while the remainder are broken down into free amino acids by peptidases on the microvillus membranes of the cell, prior to absorption in a similar way to disaccharides. These amino acids are transported into the cell by a number of different carrier systems.

Diagrammatic representation of solute transport across the apical membrane showing glucose/galactose sodium-linked transport. The Na+, K+ ATPase pump is located in the basolateral membrane.

Diagrammatic representation
of solute transport across the apical
membrane showing glucose/galactose
sodium-linked transport. The Na+, K+
ATPase pump is located in the
basolateral membrane.

Dietary fat mainly consists oftriglycerides with some cholesterol and fat-soluble vitamins. Emulsification of fat occurs in the stomach and is followed by hydrolysis of triglycerides in the duodenum by pancreatic lipase to yield fatty acids and monoglycerides. Bile enters the duodenum following gallbladder contraction. Bile contains phospholipids and bile salts, both of which are partially water soluble and act as detergents. They aggregate together to form micelles with their hydrophilic ends on the outside. Trapped in the hydrophobic centre of this micelle are the monoglycerides, fatty acids and cholesterol; these are then transported to the intestinal cell membrane. At the cell membrane the lipid contents of the micelle are absorbed, while the bile salts remain in the lumen. Inside the cell the monoglycerides and fatty acids are re-esterified to triglycerides. The triglycerides and other fat-soluble molecules (e.g. cholesterol, phospholipids) are then incorporated into chylomicrons to be transported into the lymph.

(a) The pathophysiology of fat absorption. (b) Diagram showing the formation of mixed micelles

(a) The pathophysiology of fat absorption.
(b) Diagram showing the formation of mixed micelles

The pathophysiology of fat absorption is shown . Interference with absorption can occur at all stages, as indicated, giving rise to steatorrhoea.
WATER AND ELECTROLYTES. A large amount of water and electrolytes, partly dietary, but mainly from intestinal secretions, are absorbed coupled with monosaccharides and amino acids in the upper jejunum. Some water and electrolytes are absorbed in the ileum and right side of the colon, where active sodium transport occurs but which is not coupled to solute absorption. Intestinal secretion also takes place and abnormalities of this mechanism cause secretory diarrhoea.

WATER-SOLUBLE VITAMINS, ESSENTIAL METALS

AND TRACE ELEMENTS. These all have to be absorbed in the small intestine. It must be remembered that vitamin B\2 (see p. 304) is the only substance other than bile salts that is specifically absorbed in the terminal ileum alone and malabsorption of both these substances will always occur following ileal resection.

CALCIUM

IRON.

Defence against antigens.

The normal intestinal mucosa forms an intrinsic barrier to the absorption of many antigens such as bacteria, viruses or dietary proteins. The mucosa contains scattered lymphoid cells as well as lymphoid aggregates, e.g. the tonsils and Peyer’s patches, to form the gut-associated lymphoid tissue (GALT).
Antigenic priming of the GALT can give rise to specific secretory immunity, not only in the gut but also in other mucosal-associated lymphoid tissue (MALT), e.g. respiratory tract, lacrimal, salivary and mammary glands. This is because of the migration of specifically primed T and B cells from the GALT via the local mesenteric lymph nodes, and the thoracic duct and peripheral circulation back to the lamina propria (of gut or other mucosal tissue) where they become immunoglobulin (Igj-producing plasma cells.

Small intestinal mucosa with a Peyer's patch ing the gut-associated lymphoid tissue.

Small intestinal mucosa with a Peyer’s patch
showing the gut-associated lymphoid tissue.

Local mucosal immunity is provided by the secretory immunoglobulin (sIg) system. There are approximately 1010 Ig-producing immunocytes (plasma cells and plasmoblasts) per metre of human small bowel of which 70-90% are IgA immunocytes. Dimeric and polymeric IgA (pIgA) and IgM, containing a disulphide-Iinked polypeptide called T (or ‘joining’) chain, are transported through the glandular epithelium via the transmembrane pIg receptor called ‘secretory component’ (SC) into the gut lumen. These antibodies are the first line of defence against antigens in the lumen and may take part in the immunological homeostasis within the mucosa, e.g  dampening T-cell-rnediated hypersensitivity responses against harmless absorbed luminal antigens. sc expression can be up-regulated by lymphokines, e.g. interferon-y (IFN-I’) and tumour necrosis factor-a (TNF-a) secreted by activated T cells and macro phages respectively, thus promoting the transport of IgA and IgM into the lumen.
A specialized epithelial cell above the Pey r’s patches, called the ‘M’ or ‘membrane’ cell, lacks Sc and HLA-DR expression; these cells allow non-selective inward transport of luminal antigens. Antigens may also be taken up by other epithelial cells (expressing HLA-DR) on a genetically restricted basis and may subsequently be presented directly by antigen-presenting cells (macro phages) to primed (memory) T lymphocytes. Intraepithelial lymphocytes (IEL) are mainly T cells with a predominance of TS (CDS+) cells, whereas the lamina propria contains mainly T4 (CD4+) subsets. Most human IELs express the T cell receptor a/{3 (TCRa/{3) which, along with considerable CD45RO expression, suggest that they are traditional memory T cells. Few cells express TCRy/8.

Specific conditions

CHRONIC PEPTIC ULCER. Since the advent of H2- receptor antagonists, omeprazole and the role of H. pylori in aetiology, every effort should be made to avoid surgery. If necessary to control haemorrhage the bleeding vessel is ligated, but no other surgical procedure is undertaken. Eradication of H. pylori is mandatory following a bleed.

GASTRIC CARCINOMA. Most patients do not have large bleeds with this condition but surgery may be performed for the lesion per se.
OESOPHAGEAL VARICES.
MALLORy-WEISS TEAR. This is a linear mucosal tear occurring at the oesophagogastric junction and produced by a sudden increase in intra-abdominal pressure. It often occurs after a bout of coughing or retching and is classically seen after an alcohol binge. There may, however, be no antecedent history of retching. The haemorrhage may be large but most patients stop spontaneously. Rarely, surgery with over-sewing of the tear will be required.

PROGNOSIS

The mortality of gastrointestinal haemorrhage has not changed over the years, despite many changes in management (see above) partly owing to more patients being elderly. Early endoscopy has not so far reduced the mortality, although bleeding episodes are reduced.

Acute lower gastrointestinal bleeding

Massive bleeding from the lower gastrointestinal tract is rare. On the other hand, small bleeds from haemorrhoids occur very commonly. Massive bleeding is usually due to diverticular disease or ischaemic colitis and may require urgent resuscitation. Surgery is rarely required as bleeding usually stops spontaneously. The causes of lower gastrointestinal bleeding are shown.

Causes of lower ointestinal bleeding. The sites are illustrative-many of the ns can be seen in other parts of the n.

Causes of lower
ointestinal bleeding. The sites
are illustrative-many of the
ns can be seen in other parts

MANAGEMENT

Resuscitation when required.
Make diagnosis using the following investigations as appropriate:
• Rectal examination, e.g. carcinoma
• Proctoscopy, e.g. haemorrhoids
• Sigmoidoscopy, e.g. inflammatory bowel disease
• Barium enema-any mucosal lesion
• Colonoscopy-diagnosis and removal of polyps
• Angiography-vascular abnormality, e.g. angiodysplasia
Treatment. Individual lesions are treated as appropriate.

Chronic gastrointestinal bleeding

Patients with chronic bleeding usually present with iron deficiency anaemia.
Chronic blood loss producing anaemia in all men and all women after the menopause is always due to bleeding from the gastrointestinal tract. Occult blood tests are not, therefore, necessary.

Measurement of faecal occult blood.

Measurement of faecal occult blood.

DIAGNOSIS

Chronic blood loss can occur with any lesion of the gastrointestinal tract that produces acute bleeding. In addition a Meckel’s diverticulum and carcinoma of the caecum may present with an iron deficiency anaemia. It should be remembered that, worldwide, hookworm is the commonest cause of chronic gastrointestinal blood loss.
Careful history and examination may indicate the most likely site of the bleeding, but if no clue is available it is usual to investigate both the upper and lower gastrointestinal tract endoscopically at the same session (‘top and tail’).
For practical reasons an upper gastrointestinal endoscopy is performed first as this takes minutes only. If no lesion is found this is followed by a colonoscopy as a possible lesion can be removed or biopsied. A barium enema is performed if colonoscopy is unavailable. A small bowel follow-through is the next investigation but the diagnostic yield is very low. Following a negative investigation, an angiogram may show up the site of bleeding, particularly when acute bleeding is occurring. Occasionally intravenous technetium-labelled colloid may be used to demonstrate the bleeding site in a Meckel’s diverticulum. Endoscopes to visualize the whole of the small bowel (enteroscopy) are available at specialist centres.

Acute and chronic gastrointestinal bleeding

This section should be read in conjunction with the descriptions of the specific conditions mentioned. Acute upper gastrointestinal bleeding Haematemesis is the vomiting of blood. Melaena is the passage of black tarry stools; the black colour is due to altered blood by acid-50 ml or more is required to produce this. Melaena can occur with bleeding from any lesion from areas proximal to and including the caecum. Following a massive bleed from the upper gastrointestinal tract, unaltered blood (owing to rapid transit) can appear per rectum, but this is rare. The colour of the blood appearing per rectum is dependent not only on the site of bleeding but also on the time of transit in the gut.

AETIOLOGY

Chronic peptic ulceration still accounts for approximately half of all cases of upper gastrointestinal haemorrhage. This and other causes are shown in Fig. 4.18. The relative incidences of these causes vary depending on the patient population.
DRUGS. Aspirin and other NSAIDs can undoubtedly produce gastric lesions. These agents are also responsible for gastrointestinal haemorrhage from both duodenal and gastric ulcers, particularly in the elderly. Corticosteroids in the usual therapeutic doses probably have no influence on gastrointestinal haemorrhage.

Causesof upper gastrointestinal haemorrhage. The approximate frequency is also given.

Causesof upper gastrointestinal haemorrhage. The approximate frequency is also given.

IMMEDIATE MANAGEMENT

All cases with a recent (i.e. within 48 hours) significant gastrointestinal bleed should be admitted to hospital. In many, no further immediate treatment is required as the patient’s cardiovascular system can compensate for the blood loss. Approximately 85% of patients stop bleeding spontaneously within 48 hours. Factors affecting management are:
• Age (see below).
• The amount of blood lost, which may give some guide to the severity.
• Continuing visible blood loss.
• Signs of chronic liver disease on examination, as the bleeding is often severe and recurrent if it is from varices; liver failure can develop.

• Presence of the classical clinical features of shock (i.e. pallor, cold nose, tachycardia and low blood pressure) (Emergency box 4.1); remember that the peripheral constriction that occurs may keep the blood pressure falsely high.
Urgent resuscitation is required in patients with large bleeds and the clinical signs of shock. Details of the management of shock are given in Emergency box 13.1,. Many hospitals have multidisciplinary specialist teams with agreed protocols and these should be carefully followed. The major principle is to restore the blood volume to normal rapidly. This can be best achieved by transfusion of whole blood via one or more large bore intravenous cannulae. It may be necessary in a severely shocked patient or in a patient with blood compatibility problems to give a blood substitute initially.
The rate of blood transfusion must be monitored carefully to avoid overtransfusion and consequent heart failure. The pulse rate and venous pressure are the best guides to transfusion rates.
Anaemia does not develop immediately as haemodilution has not taken place and therefore the haemoglobin level is a poor indicator of the need to transfuse. If the level is low « 10 g dl-I ) and the patient has eitherbled recently or is actively bleeding, transfusion may be necessary.
In most patients the bleeding stops, albeit temporarily, so that further assessment can be made.

Indications for blood transfusion

Indications for blood transfusion

Important factors in reassessment

• Age-below the age of 60 years mortality from gastrointestinal bleeding is small. Above the age of 80 the mortality is greater than 20%.

• Recurrent haemorrhage-these patients have an increased mortality.
• Most re-bleeds (approximately 25% of all cases) occur within 48 hours.
• Melaena is usually less hazardous than haematemesis.

FUTURE MANAGEMENT

The cause of the haemorrhage may be obvious from the history, e.g. a long history of indigestion or, more significantly, previous haemorrhage from an ulcer. A history of aspirin or NSAID ingestion suggests acute ulceration. Signs of chronic liver disease, particularly with splenomegaly, suggest bleeding from oesophageal varices. The source of haemorrhage in most patients with chronic liver disease is their varices, but occasionally they may bleed from an accompanying peptic ulcer. The absence of splenomegaly does not rule out oesophageal varices.

ENDOSCOPY should be performed as soon as practically possible, but urgently in patients with suspected liver disease or with continued bleeding. Endoscopy can detect the cause of the haemorrhage in 80% or more of cases. In patients with a peptic ulcer, if the stigmata of a recent bleed are seen, i.e. a visible vessel or adherent clot, the patient is more likely to re-bleed.
At endoscopy:
• Varices should be injected- for management of varices.
• All bleeding ulcers should be either injected with adrenaline and a sclerosant or the vessel coagulated either with a heater probe or with laser therapy. These methods reduce the incidence of re-bleeding, although they do not significantly improve mortality.
MOST CONDITIONS require no specific therapy after resuscitation. There is little evidence that Hj-receptor antagonists affect the mortality rate of gastrointestinal haemorrhage, but these agents are usually given to patients with ulcers because of their longer term benefits.
RE-BLEEDS. Endoscopy should be repeated to reassess the bleeding site and to treat, if possible. Surgery is only necessary if bleeding is persistent or recurrent, and if it cannot be controlled.
DISCHARGE POLICY. Patients under the age of 60 years with duodenal ulceration, who are haemodynamically stable and have no stigmata of recent haemorrhage on endoscopy can be discharged from hospital within 24 hours.