The daily dietary intake of an adult consists, on average, of 70 g protein, 100 g fat, and 300 g carbohydrate. The average fluid intake is 1.5 l in 24 h and about 7 l of endogenous secretions enter the small intestine. The digestive and absorptive capacity is such that only 500 to 700 ml passes into the colon from the ileum during a 24-h period and the average stool weight on a Western diet is 150 to 200 g (Fig. 1) 983.

The major dietary carbohydrates comprise starch, disaccharides (sucrose and lactose), and monosaccharides (glucose and fructose). Salivary and pancreatic amylases split the 1-4&agr;-glucosidic linkages of the starch to liberate maltose. Further digestion and absorption of the disaccharides is achieved by the action of the oligosaccharidases (lactase, sucrase, maltase) which are globular proteins within the brush border of the enterocyte. The glucose and galactose released by these enzymes are transported into the cell by Na⫀-dependent specific transporter proteins. Fructose transport occurs by facilitated diffusion and is not Na⫀ dependent.

Protein digestion begins in the stomach, where secreted pepsinogen becomes activated by an acid pH, and continues in the duodenum and jejunum by pancreatic proteases. These are again secreted in their inactive form (trypsinogen, chymotrypsinogen) and are activated by enterokinase, an enzyme secreted by the duodenal mucosa. This intraluminal digestion results in the release of small peptides containing two to four amino acids. Further digestion occurs by the action of peptidases located in the brush border. Dipeptides can be absorbed by a specific transport system following hydrolysis by dipeptidases, whereas the absorption of free amino acids is achieved by a number of mechanisms, all of which are Na⫀ dependent and hence require energy.

Most of dietary fat is in the form of triglycerides, which contain three long chains of fatty acid linked to glycerol. The first step in fat digestion is hydrolysis by pancreatic lipase which splits two of the fatty acid chains from the &agr;-positions of the glycerol molecule leaving a &bgr;-monoglyceride. The second step depends on the formation of micelles by the bile salts which carries the long chain fatty acids and the monoglyceride into the water phase and hence to the lipophilic surface of the enterocyte. At this point, the micelles disaggregate and the free fatty acids and the monoglyceride pass through the brush border into the cytoplasm by mechanisms which are poorly understood. Once in the cytoplasm, a series of reactions involving cholesterol leads to the synthesis of chylomicrons and very low density lipoproteins.

The presence of adequate concentrations of bile salts in the small intestinal lumen is therefore crucial for fat absorption. In man the primary bile acids are cholic acid (a trihydroxy bile acid) and two dihydroxycholic acids, chenodeoxycholic and deoxycholic acid, which are conjugated to taurine or glycine to form the bile salts. The majority of bile salts secreted into the bile are reabsorbed from the ileum and recycled—this occurs 10 times on average in a 24-h period. The total pool of bile salts is about 2 to 4 g and the 24-h synthesis rate is about 600 mg: this makes up for faecal losses. It follows, therefore, that fat malabsorption may occur as a result of either cholestasis or ileal disease or resection which causes increased bile salt loss. When the liver synthesizes less bile salts than are lost, the intestinal concentration falls to a point below the minimal micellar concentration and fat malabsorption results. Two other mechanisms will potentially lower the bile salt concentration in the lumen. Firstly, at normal jejunal pH, the bile salts are present in ionized form. If the pH falls (for example, in the Zollinger–Ellison syndrome) the bile salts become non-ionized and are then absorbed by passive non-ionic diffusion. Secondly, bacteria (especially anaerobes) are able to deconjugate bile salts, leading to the steatorrhoea which occurs in association with bacterial overgrowth of the small intestine.

Most minerals and vitamins are absorbed from the proximal jejunum. Vitamins A, D, and K are fat soluble and dependent on the normal mechanism of fat absorption; malabsorption therefore occurs in the presence of steatorrhoea. Iron is absorbed from the duodenum by a carrier-mediated process which is controlled by the body's iron stores and which involves mechanisms which are not clearly defined; thus, iron absorption increases in the presence of iron deficiency. Folic acid is present as polyglutamates in the diet and these are hydrolysed to monoglutamates by folate deconjugase, another brush border enzyme. Calcium, like iron, is absorbed in the duodenum and proximal jejunum by a carrier-mediated process involving calcium-binding protein and a calcium-activated ATPase. The synthesis of the calcium-binding protein is under the control of 1,25-dihydroxy cholecalciferol (1–25 (OH&sub2;)D&sub3;).

Vitamin B&sub1;&sub2; is only absorbed from the terminal ileum and in order for it to combine with its specific receptor on the enterocyte surface it has to be complexed with intrinsic factor, a glycoprotein synthesized by the gastric parietal cells. Deficiency of intrinsic factor, either due to subtotal gastric resection or to autoimmune mechanisms as in pernicious anaemia, causes vitamin B&sub1;&sub2; malabsorption. Vitamin B&sub1;&sub2; malabsorption also results from ileal disease (such as Crohn's disease) or from ileal resection, due to loss of enterocyte receptors for the vitamin B&sub1;&sub2;–intrinsic factor complex.

The small intestine has considerable reserve capacity since, as previously mentioned, absorption mainly occurs in the jejunum with only fat, bile salts and vitamin B&sub1;&sub2; being absorbed from the ileum. Studies in experimental animals, as well as observations in humans following small intestinal resection, have shown that the ileum can undergo hypertrophy, which increases its absorptive capacity very considerably. This contrasts with the proximal small intestine, which has only a limited capacity to adapt. Thus, resection of the jejunum may not necessarily cause malabsorption whereas ileal resection inevitably causes malabsorption of vitamin B&sub1;&sub2; and bile salts. If more than 100 cm of ileum is resected, bile salt malabsorption becomes sufficiently severe for hepatic synthesis to fail to maintain the circulating pool and fat malabsorption occurs.

These include weight loss, malaise and lassitude, anorexia, and symptoms of anaemia. There may also be evidence of hypoalbuminaemia with dependent oedema and skin changes. Finger clubbing is common in patients with long-standing malabsorption such as coeliac disease. Aphthous ulcers in the mouth are frequently present in patients with coeliac disease or Crohn's disease.

This usually, although by no means always, has the features of a steatorrhoea. The stools become bulky, pale, and offensive. Their high fat content causes them to float and they are difficult to flush away. Stool frequency may be increased. However, many patients with malabsorption may not complain of an altered bowel habit.

Symptoms of excess wind, abdominal distension, borborygmi, and varying degrees of discomfort are common. If the diarrhoea is not typically a steatorrhoea, these symptoms may be diagnosed as an irritable bowel syndrome. The combination of abdominal distension and wasting may give rise to a marked ‘pot-belly’, particularly in children.

The physical signs of iron deficiency are common and include a glossitis, angular stomatitis (Fig. 2) 984, brittle nails, and a dry skin. Neurological complications of vitamin B&sub1;&sub2; deficiency (dementia, peripheral neuropathy, subacute combined degeneration of the spinal cord) are rarely seen except in patients with a severe pernicious anaemia. Proximal myopathy may result from osteomalacia or hypokalaemia. Bone pain and positive Chovstek's and Trousseau's signs may indicate osteomalacia and the last two signs may also be caused by hypomagnesaemia. Bruising may indicate vitamin K deficiency. Night blindness as a result of vitamin A deficiency is rare but is probably more common than is recognized. Pigmentation is common.

Investigation of a patient with suspected malabsorption is directed towards documenting the nature and severity of the malabsorption and defining the cause.

Table 1 316 lists the investigations that will allow the degree of malabsorption to be assessed. The presence of fat malabsorption, and therefore of vitamins A, D, and K, but with normal serum concentrations of iron and folate, is highly suggestive of a pancreatic aetiology rather than a mucosal cause. This can be confirmed with a d-xylose test: this test, performed on a 5-h urine collection and a 1-h serum sample following the ingestion of 25 g of xylose, will detect patients with mucosal abnormalities causing malabsorption with a high degree of specificity and sensitivity. An abnormal test result may be due, however, to inadequate urinary collection, delay of gastric emptying or interference by drugs such as aspirin, neomycin, or non-steroidal anti-inflammatory drugs.

Estimation of faecal fat excretion is crucial in order to document steatorrhoea, and this should be performed on a 3-day stool collection. Unfortunately an increasing number of clinical laboratories are refusing to provide this assay despite the recent development of closed systems for faecal collection and homogenization. Staining faecal smears with appropriate stains (such as Oil Red O) can detect an excess of fat globules and this qualitative test has shown good correlation with the quantitative assay. However, the qualitative test is unreliable in patients with mild steatorrhoea (<10 g/24 h). The ¹&sup4;C-triolein breath test can also be used to assess fat absorption, but this suffers from the disadvantages of an 8-h duration and the need to administer a test meal containing 60 g of fat.

This is the definitive test for most causes of mucosal malabsorption. It is essential for the diagnosis of coeliac disease, tropical sprue, and intestinal lymphangiectasia and is diagnostic for malabsorption caused by amyloidosis, Whipple's disease, &agr;-chain disease, and parasitic infestations (giardiasis, cryptosporidiosis). Endoscopic biopsies from the distal duodenum are increasingly being used and they appear to be as useful as jejunal biopsies taken with the Crosby capsule. The steerable Medi-Tech biopsy capsule is much quicker than the Crosby capsule and two or three biopsy specimens can be obtained. For multiple biopsies from differing sites, the Quinton hydraulic machine has to be used (Fig. 3) 985.

Contrast examination of the small intestine is best performed using a small bowel enema. It is essential for detecting anatomical abnormalities (such as jejunal diverticulosis), strictures (as in Crohn's disease, radiation enteritis, ischaemia, systemic sclerosis, lymphomas, carcinoma) or motility disorders (pseudo-obstruction, systemic sclerosis).

These imaging modalities are primarily useful for detecting biliary, pancreatic, or hepatic disease. CT scans may also detect infiltration of the small intestinal wall (such as lymphoma) and enlarged mesenteric nodes.

Hypolactasia is best diagnosed by biochemical assay of lactose activity in a jejunal biopsy specimen. However, this assay is not widely available and the lactose breath test provides a simple, rapid and non-invasive alternative. The hydrogen concentration in a sample of end-expiratory air is measured before and 2 h after a 50 g dose of lactose given to a fasting patient. A rise of greater than 20 ppm of H&sub2; indicates hypolactasia.

Bacterial overgrowth of the small bowel can be detected using the lactulose breath test. Lactulose is a non-absorbed disaccharide which usually passes into the colon where it undergoes bacterial fermentation. Much of the released hydrogen is absorbed and expired and in a normal subject there is a rise in breath hydrogen after 90 to 150 min, which represents small intestinal transit time. Bacterial overgrowth of the small bowel is associated with an early rise of breath hydrogen (at 15–45 min) (Fig. 4) 986. Obviously, the test can be misleading in patients with altered transit times. The ¹&sup4;C-glycocholate breath test may also be used and relies on the ability of bacteria to deconjugate the bile salt. Aspiration of jejunal contents for microbiology can be used but meticulous technique is required if this is to be reliable.

Measurement of serum immunoglobulins are essential for the diagnosis of hypogammaglobulinaemia. The presence of antibodies to reticulin or gliadin supports the diagnosis of coeliac disease, but is not diagnostic. Likewise, antibody to intrinsic factor in serum is highly suggestive of pernicious anaemia. Selective immunoelectrophoresis of saliva, serum, urine, or jejunal aspirate is required to diagnose the free &agr;-chains characteristic of &agr;-chain disease.

There are numerous causes of malabsorption and it is convenient to divide them into those involving a failure of intraluminal digestion and those where there is a failure of mucosal absorption. Table 2 317 lists some of the major causes.

This may be due to intrahepatic or extrahepatic causes: the former include primary biliary sclerosis, alcohol, drugs or viral hepatitis, the latter benign or malignant biliary strictures, ampullary or pancreatic tumours, and bile-duct stones. Chronic pancreatitis may also result in obstruction of the lower end of the common bile duct, giving rise to a typical ‘rat-tail’ stricture which can be seen at endoscopic retrograde cholangiopancreatography (ERCP). Primary sclerosing cholangitis can involve both intrahepatic and extrahepatic ducts. Whatever the cause of cholestasis, malabsorption is caused by bile salt insufficiency, and patients therefore develop steatorrhoea and the accompanying malabsorption of the fat soluble vitamins (A, D, K).

This is usually caused by chronic pancreatitis or by proximal obstruction to the pancreatic duct by tumour, and results in steatorrhoea and malabsorption of the fat soluble vitamins. The secretory capacity of the pancreas has to be reduced to less than 10 per cent of normal before malabsorption develops.

Inadequate mixing of food with bile and pancreatic secretions may occur after a Polya gastrectomy, gastroenterostomy, or a Roux-en-Y procedure. This may give rise to a degree of maldigestion but, if frank malabsorption occurs, other factors such as bacterial overgrowth may also be involved.

The mechanisms involved in fat malabsorption caused by bacterial overgrowth are discussed above. Bacteria may also compete with the host for vitamin B&sub1;&sub2;, resulting in the development of a megaloblastic anaemia. The proximal small intestinal flora is usually less than 10&sup4; organisms/ml: bacterial counts greater than this constitute bacterial overgrowth. This is found in many small bowel diseases, including Crohn's disease, jejunal diverticulosis, strictures, autonomic neuropathies, or other causes of pseudo-obstruction. Bacterial overgrowth will also complicate a ‘blind-loop’ such as the afferent limb of a Polya gastrectomy or an end-to-side anastomosis (Fig. 5) 987, or internal enteric fistulae (especially gastrocolic or ileocolic). Recently, it has been recognized that elderly patients may develop bacterial overgrowth and malabsorption in the absence of any demonstrable anatomical abnormality. In some patients with bacterial overgrowth (for example, those with jejunal diverticulosis) the small bowel mucosa may show some loss of villous height and a chronic inflammatory infiltrate, but this is never as severe as the mucosal changes seen in coeliac disease.

Jejunal diverticulosis (Fig. 6) 988 occurs in the elderly and is usually asymptomatic unless bacterial overgrowth is sufficient to cause steatorrhoea. When this occurs antibiotics should be given, as for any cause of bacterial overgrowth. Metronidazole is the drug of choice, but since many of these patients will require repeated courses, which may induce resistant organisms, doxycycline and neomycin can be used in rotation with metronidazole. The complications of jejunal diverticulosis, in addition to malabsorption, are a silent perforation (which needs no specific treatment) and volvulus (which requires resection). Only very rarely does an acute diverticulitis develop; this should, in the first instance, be treated with intravenous fluids and antibiotics.

Autonomic neuropathy of the intestine is usually seen in association with diabetes mellitus but other causes include vincristine, spinal cord injury, Shy–Drager syndrome, amyloidosis, and systemic sclerosis. Other signs of autonomic neuropathy, such as postural hypotension and a fixed R-R interval on a Valsalva manoeuvre, are nearly always present. Apart from controlling bacterial overgrowth, management consists of symptomatic control of diarrhoea and nutritional support.

The drug in common usage which may rarely cause malabsorption is neomycin, which appears to cause steatorrhoea by precipitating bile salts. Cholestyramine can also increase fat excretion by binding bile salts.

Coeliac disease predominantly affects children and young adults, although it may occur at any age. The incidence varies considerably, being present in about 1 in 5000 to 7000 of the population in the West but being exceptionally rare in other parts of the world. This distribution may be explained by the very close association of coeliac disease with HLA antigens. Approximately 95 per cent of patients with coeliac disease are HLA-DQ2 and over 80 per cent have the haplotype B8, DR3, DQ2. Thus, the aetiology of coeliac disease represents an interplay between genetic factors and the ingestion of gluten. Nevertheless, the fact that there is 30 per cent discordance amongst monozygotic twins suggests that other factors are important in initiating the disease. Recently, there has been considerable interest in the role of adenovirus 12 as an initiating factor because there is sequence homology between an epitope in an ‘early protein’ (E1b) of the virus and a surface epitope of a gliadin fraction (gliadin is prepared from gluten by alcohol extraction). Coeliac patients show cellular immune responses to both viral and gliadin epitopes and the gliadin epitope has been shown to be toxic in in-vivo challenge studies. Hence, it is possible that exposure to this virus in a person with the genetic susceptibility to develop coeliac disease may break oral tolerance to gluten and allow a harmful mucosal immunological reaction to occur.

Although patients with coeliac disease may still present with the classical clinical picture of weight loss, anorexia, steatorrhoea, and the signs of nutritional deficiency, the majority of patients are now diagnosed at a much earlier stage: unexplained iron deficiency anaemia or the symptoms of an irritable bowel syndrome are the most frequent presenting features. Any patient who presents with a variable bowel habit, abdominal pain, distension, and wind, who has lost weight or who also complains of aphthous ulcers of the mouth should undergo a small intestinal biopsy. This will show severe villous atrophy with crypt hyperplasia in affected individuals. Treatment consists of a gluten-free diet. Patients should be instructed by dietitians and, ideally, should also become members of a national coeliac society, which continually provides their members with information on the gluten status of new food products and disseminates knowledge about the disease. A repeat biopsy should be obtained after 3 to 4 months of dietary treatment to check that the mucosa has returned towards normal. The strict definition of coeliac disease requires a gluten challenge with repeat biopsy, but this is usually reserved for patients in whom the diagnosis may be in doubt. Patients will need to be on a gluten-free diet for life and should adhere to it strictly. A visit to a specialized clinic is recommended at least once a year.

Adherence to a strict diet not only achieves maximal histological remission, but may avoid the long-term complications of coeliac disease, namely an ulcerating jejunoileitis or a mucosal T-cell lymphoma. Carcinomas of the gastrointestinal tract, especially the oesophagus, are also associated with coeliac disease but whether strict dietary control influences the incidence of carcinoma is less clear.

Patients who have clear evidence of nutritional deficiencies (e.g. iron, folate, vitamins K or D) will need replacement therapy initially, but once the jejunal mucosa returns to near normal there should be no need for long-term supplements. If the coeliac disease is severe, affecting a substantial part of the small intestine (indicated by a marked steatorrhoea) patients may also benefit from lactose withdrawal until the brush border of the enterocytes have recovered on the gluten-free diet.

Some patients (<10 per cent) who appear to have coeliac disease do not show histological recovery on gluten withdrawal even after many months. The usual reason is lack of dietary compliance. However, if this has been excluded, other conditions should be considered. These include collagenous sprue (the biopsy shows >12 &mgr;m subepithelial collagen band and, usually, hypoplastic crypts), lymphoma, hypogammaglobulinaemia, amyloidosis, tropical sprue, chronic ischaemia, or Whipple's disease. Other conditions such as Crohn's disease, tuberculosis, systemic sclerosis, and radiation enteritis may also be associated with a flat mucosal biopsy but there is usually obvious evidence of these diseases on barium radiology.

IgA deficiency is the most common immunodeficiency disorder, and may be symptomless or associated with recurrent upper respiratory tract infections, sinusitis and skin sepsis. It also affects about 10 per cent of patients with coeliac disease.

Common variable hypogammaglobulinaemia, in which there is a variable depression of serum IgA, G, and M, is also associated with a flat small intestinal mucosa which does not usually respond to gluten withdrawal. Many of these patients develop giardiasis or cryptosporidiosis, and bacterial overgrowth is common. Treatment involves eradication of infection and patients may benefit from a lactose-free diet.

AIDS is associated with a lack of mucosal CD4⫀ cells in parallel with the fall in circulating CD4⫀ lymphocytes. Hence, degrees of mucosal abnormalities are common in these patients and opportunistic infections may contribute to the mucosal damage and subsequent malabsorption.

1.The so-called Western lymphoma is usually a focal tumour (Fig. 7) 989. It is a B-cell lymphoma, mainly centrocytic or centroblastic in type.

2.A diffuse lymphoma (Mediterranean type). This usually causes ‘&agr;-chain’ disease, in which the abnormal clone of B cells gives rise to plasma cells which synthesize and release free &agr; chains of IgA without the accompanying light chain. The disease causes profound malabsorption. Diagnosis is made by a small intestinal biopsy and by the demonstration of free &agr; chains in serum, saliva, jejunal aspirate, or urine.

3.T-cell lymphoma may also complicate coeliac disease.

This usually results from massive surgical resection following mesenteric infarction or from repeated resections for Crohn's disease. Malabsorption occurs because there is loss of absorptive surface. However, there may be bacterial overgrowth or there may be a degree of mucosal abnormality leading to hypolactasia.

Management involves correction of bacterial overgrowth, a lactose-free diet (if necessary, and diet may need to be low in disaccharides generally if there is severe brush border damage), and full dietary supplements, together with intramuscular administration of vitamin B&sub1;&sub2; (250 &mgr;g every 3 months). Some patients will require home parenteral nutrition to maintain body weight and an adequate intake of minerals and vitamins.

The primary management is to treat the cause of the malabsorption: pancreatic enzymes must be given for pancreatic insufficiency, a gluten-free diet for coeliac disease, antibiotics for bacterial overgrowth. In these instances, there is usually no need for long-term nutritional supplements provided the malabsorption is corrected adequately. However, in the acute stage replacement with vitamins, iron, calcium, magnesium, and zinc may be necessary.

For patients in whom the cause of malabsorption cannot be corrected, management may require oral supplements of B vitamins, iron and folate. All patients with ileal resections are at risk from vitamin B&sub1;&sub2; deficiency and may need supplementation—250 &mgr;g vitamin B&sub1;&sub2; given intramuscularly every 3 months is sufficient. Patients with continuing steatorrhoea, including those with prolonged cholestasis, extensive mucosal atrophy of the small bowel, and those with a short bowel syndrome, will suffer from malabsorption of vitamins A, D, and K. Monthly intramuscular injections of these fat soluble vitamins may be needed (e.g. vitamin A 10000 U, vitamin D 100000 U, vitamin K 10 mg). Dietary management will include a low fat diet, for those with prolonged steatorrhoea, and supplements of carbohydrate and protein. However, if there is extensive villous atrophy these supplements will need to be in the form of glucose and tri- or dipeptides which can be absorbed directly without requiring enzymatic digestion. Medium chain triglyceride should also be given as a way of providing fat in a steadily absorbable form.

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