Clues to the cause of the diarrhoea can be obtained from the history and examination (Table 14.1). Small-volume, frequent stools suggest large bowel disease and tenesmus (a constant sense of the need to defecate) suggests rectal involvement. Large-volume, watery stools are consistent with small bowel disease, whereas obvious clinical steatorrhoea with pale, bulky, oily stools that float suggests the presence of small bowel or pancreatic disease.

Table 14.1 Clinical features in chronic diarrhoea

Clinical feature	Conditions to consider
Young age	Coeliac disease, inflammatory bowel disease, lactase deficiency, irritable bowel syndrome
Oil droplets in stool	Pancreatic insufficiency
Previous surgery	Bacterial overgrowth, dumping, post vagotomy diarrhoea, ileal resection, short bowel syndrome
Peptic ulcer	Zollinger-Ellison syndrome
Medications	Laxatives, magnesium antacids, antibiotics, lactulose, colchicine
Frequent infections	Immunoglobulin deficiency
Marked weight loss	Thyrotoxicosis, malignancy, malabsorption
Arthritis	Inflammatory bowel disease, Whipple’s disease, hypogammaglobulinaemia, Yersinia spp.
Hyperpigmentation	Whipple’s disease, Addison’s disease, coeliac disease
Fever	HIV, inflammatory bowel disease, lymphoma, Whipple’s disease
Flushing	Carcinoid syndrome
Chronic lung disease	Cystic fibrosis
Neuropathy	Diabetes mellitus, vitamin B₁₂ deficiency, amyloidosis
Family history of diarrhoea	Colon cancer, coeliac disease, inflammatory bowel disease

The presence of blood may indicate local anal bleeding or other colonic disease. Bright red blood that is separate from the stool is consistent with an anal or rectal cause, but may occur with more proximal colonic disease. Altered blood, or blood with the stool is in keeping with higher colonic bleeding, such as from inflammatory bowel disease or colon cancer (Ch 10).

Symptoms associated with the diarrhoea may also provide valuable information about the nature of the underlying disease process. Weight loss suggests an organic disorder and may be marked with malabsorption, carcinoma or inflammatory bowel disease. Large joint arthritis or sacroileitis suggests inflammatory bowel disease. Yersinia infection and Whipple’s disease can also present with arthritis.

Symptoms of individual nutrient deficiencies (like easy bruisability with vitamin K deficiency, night blindness with vitamin A deficiency, tetany and osteomalacia with vitamin D deficiency and stomatitis, angular cheliosis, glossitis and anaemia with iron and B group vitamin deficiency) not only help separate functional from organic diarrhoea but also may provide aetiological clues.

The presence of a skin rash may suggest coeliac disease (e.g. dermatitis herpetiformis) or inflammatory bowel disease (e.g. erythema nodosum or erythema multiforme). Crampy abdominal pain occurs with diarrhoea of any cause, but pain shortly after eating raises the possibility of partial bowel obstruction (e.g. Crohn’s disease or bowel cancer). Abdominal pain is also a feature of chronic pancreatitis, associated with malabsorption. Abdominal bloating may occur with most forms of diarrhoea but, in association with alternating diarrhoea and constipation, suggests the presence of the irritable bowel syndrome. The duration of symptoms may also be helpful, as diarrhoea occurring over many years is more in keeping with a benign process.

There may be a correlation between diarrhoea and diet. Milk consumption in lactose-intolerant individuals or sorbitol intake (in chewing gum and fruit juices) can cause diarrhoea. Changing to a high-fibre diet may also cause a change in bowel habit with loose stools.

A history of systemic disease may be relevant. Disorders such as diabetes mellitus and hyperthyroidism may present with diarrhoea.

Previous surgical history including gastrectomy (postvagotomy diarrhoea and dumping syndrome), small bowel resection, bariatric surgeries and cholecystectomy must be obtained.

A drug history may identify the cause of diarrhoea; a wide variety of medications have been implicated. Antibiotics and antacids are frequent offenders in this category. Non-steroidal anti-inflammatory drugs (by causing ileal damage and bile salt malabsorption), metformin and several cardiac drugs (antiarrthymics, antihypertensives and diuretics) are other commonly used offenders and should be sought in the history. Alcohol is also a cause of chronic diarrhoea and surreptitious laxative abuse needs to be considered in difficult cases.

A sexual history is important in the evaluation of a chronic diarrhoeal illness, as diarrhoea is a very common symptom in patients with HIV/AIDS. Overseas travel before the onset of diarrhoea may implicate a gastrointestinal infection or, more frequently, a postinfectious irritable bowel syndrome.

The family history should be obtained as inflammatory bowel disease, bowel cancer and coeliac disease have an increased incidence in families.

Physical Examination

Evidence of malnutrition and wasting should be sought and the skin examined for rashes, pigmentation and evidence of nutritional deficiency. There may be evidence of iron deficiency (pallor, cheilosis, glossitis and koilonychias) or vitamin B₁₂ deficiency (peripheral neuropathy, glossitis and knuckle pigmentation). Protein deficiency may result in peripheral oedema and white nails.

Signs of thyrotoxicosis including tachycardia, systolic hypertension, sweating and tender thyroid nodule should be checked as well as all lymph node groups examined as a clue to lymphoma, malignancy and other chronic infections.

Further clues to the cause of diarrhoea may be obtained from abdominal examination. An abdominal mass or liver secondaries may be identified. A rectal mass may be present on rectal examination, or faecal impaction, particularly in elderly patients, may be noted and sphincteric tone should be tested to rule out faecal incontinence. Perianal disease with fissures, fistulae and abscesses is common in Crohn’s disease (Ch 12).

Assessment

The history and physical examination will often direct the order and nature of investigations.

Categorising the pattern of diarrhoea into osmotic (ceases on fasting), secretory (persists in fasted state), inflammatory (passage of blood) and classical steatorrhoea helps in directing investigations though overlap can occur. (See Figs 14.1 and 14.2.)

Figure 14.1 Flow chart 1.

Adapted from Fine, KD, Schiller, LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464.

Figure 14.2 Flow chart 2

From Fine, KD, Schiller, LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464.

Approach to Chronic Diarrhoea

In those in whom the diagnosis is not obvious, a variety of factors will influence the order and extent of investigations, especially the age of the patient and the length of the history. A long history suggests a benign illness, although disorders, such as coeliac disease and Crohn’s disease, may not be diagnosed for many years because of subtle symptoms. Conversely, the development of new symptoms in a patient over the age of 40 years would raise concern about the possibility of bowel cancer.

A full blood count and erythrocyte sedimentation rate (ESR) is a simple initial blood investigation and may provide information about anaemia due to iron, folate or vitamin B₁₂ deficiency. It may also show an elevated white cell count or ESR, suggesting the presence of inflammation. The serum albumin will often be low with chronic inflammatory process or with malnutrition.

The stool examination may provide information about parasites, such as Giardia lamblia, and may also document white blood cells implicating inflammation or infection, or red blood cells in bleeding (e.g. carcinoma). The stool weight provides some evidence of the severity of diarrhoea.

Sigmoidoscopy may establish the presence of inflammation or tumours. A biopsy should always be performed in patients with diarrhoea to exclude microscopic or collagenous colitis. Melanosis coli may be obvious macroscopically and will also be demonstrated on biopsy. A colonoscopy requires a full bowel preparation with sedation, but has the advantage of examining the entire bowel length and often the terminal ileum can be intubated as well. Disorders that may require colonoscopy for diagnosis include bowel cancer, polyps, segmental colitis and terminal ileitis.

Radiological investigations that may aid in the investigation of diarrhoea include a plain abdominal x-ray, small bowel series, barium enema, virtual computed tomography (CT) colonography and abdominal CT scan.

If small bowel disease is suspected, a small bowel biopsy (usually performed endoscopically) may provide further information. A disaccharidase assay can be carried out at the same time as a small bowel biopsy and bacterial culture.

Further investigations that may be needed if no diagnosis is reached include stool examination for laxatives and blood tests for thyroid function (thyroid-stimulating hormone) and hormone-secreting tumours (e.g. gastrin and vasoactive intestinal polypeptide).

Malabsorption

The basic physiological problem the body faces in assimilation of food is the passage of nutrients across the limiting cell membrane of the enterocyte. The problem is solved by breaking food particles down to basic components (digestion) and the insertion of special carrier proteins into the absorptive cells to facilitate absorption. The term ‘malabsorption’ is generally used to encompass both impaired digestion and defective absorption. A classification of malabsorption is shown in Box 14.1.

Physiology

Understanding malabsorption requires knowledge of the physiology of normal digestion and absorption.

Clinical Approach to the Patient with Malabsorption

Diagnosis in malabsorption requires firstly suspecting its presence, secondly confirming its existence and thirdly demonstrating the cause (Table 14.2).

Table 14.2 Typical test results in malabsorption

Suspecting malabsorption

Suspecting the presence of malabsorption may be easy when it is gross, but early symptoms are often subtle and non-specific. The diagnosis is usually considered in patients with marked weight loss and the presence of typical steatorrhoea: pale, bulky offensive stools that are difficult to flush and may contain oil. Anaemia is common and may be due to malabsorption of vitamin B₁₂, folate or iron. Deficiency of fat-soluble vitamins may cause bruising (vitamin K), tetany and bone pain (vitamin D), or hyperkeratosis of the skin. Night blindness may occur with vitamin A deficiency.

Protein deficiency may result in muscle wasting and oedema from hypoalbuminaemia. Peripheral neuropathy may occur following vitamin B₁₂ deficiency.

Early malabsorptive symptoms are often non-specific and may include minor weight loss, general malaise, loss of energy and a slight change in bowel habit. Presentation with a single-nutrient deficiency (e.g. iron deficiency anaemia) is quite common. Aphthous ulcers, glossitis and cheilosis may also occur. Presentation in children is usually with diarrhoea, irritability and growth failure.

Confirming malabsorption

Faecal fat excretion

The 3-day faecal fat estimation remains the ‘gold standard’ for malabsorption. A 100 g fat per day diet must be maintained for 3 days prior to and during the stool collection for accurate results. Fat excretion of more than 7 g per day is considered abnormal.

Qualitative estimation of faecal fat by staining faecal smears with Sudan III is simpler but less sensitive.

Breath tests

The triolein breath test for fat malabsorption involves the ingestion of ¹⁴C-labelled triolein and measures of ¹⁴CO₂ in the expired air. Its lack of sensitivity has limited its clinical use.

Hydrogen breath tests have been used to measure carbohydrate malabsorption. In the mammalian body, hydrogen is produced only by bacterial action, usually on unabsorbed carbohydrate in the colon. Thus if a carbohydrate that is normally absorbed in the small intestine is malabsorbed, a breath hydrogen peak will occur about 90 minutes after its ingestion when it first arrives in the colon and is broken down by bacterial action. Similarly small bowel bacterial overgrowth will be detected by an early hydrogen peak. Malabsorption of lactose or a standard rice meal can be detected in this way. Unfortunately, the limited sensitivity and specificity of breath hydrogen tests restrict their usefulness.

D-xylose test

This test measures small bowel mucosal absorption and involves the ingestion of D-xylose and measuring its excretion in the urine. As well as mucosal absorption, bacterial action, renal function, the completeness of urine collection and the action of drugs can influence the results.

Nutritional status

Nutritional status can be determined by the body mass index, mid-arm circumference and skin-told thickness. Blood tests that have been used to asses nutritional status include serum albumin, transferrin, serum prealbumin and lymphocyte count. Specific nutrient deficiencies should be sought by serum iron studies, vitamin B₁₂ and folate levels, calcium, international normalised ratio (vitamin K) and vitamin assays (A, D and E). A full blood count may document anaemia, macrocytosis, microcytosis or a mixed picture or even the presence of hypersplenism (seen in coeliac disease).

Finding the cause of malabsorption

History

The list of causes of malabsorption (Box 14.2) is daunting, and a thorough history is essential to target investigations. Common causes of malabsorption include coeliac disease, chronic pancreatitis, small bowel bacterial overgrowth and gastric surgery.

A cause may be obvious from the history if gastric surgery or a small bowel resection has been performed or there is known chronic pancreatitis. Childhood diarrhoea, failure to thrive or anaemia may suggest the possibility of coeliac disease. An associated skin rash of dermatitis herpetiformis (Fig 14.3) or a positive family history may also be clues to the diagnosis of coeliac disease.

Figure 14.3 Dermatitis herpetiformis. Typically, the lesions are grouped and distributed over the scapulae, sacrum and buttocks (A), elbows and knees. Severe pruritus accompanies the disease and results in much excoriation and ‘dug-out’ skin (B).

From Misiewicz JJ, Bantrum CI, Cotton PB, et al. Slide atlas of gastroenterology. London: Gower Medical Publishing; 1985, with permission.

Abdominal pain, alcohol excess or a history of passing ‘oil’ suggests chronic pancreatitis. Abdominal pain may also be a feature of Crohn’s disease and there is sometimes a positive family history of inflammatory bowel disease. Intestinal lymphoma and mesenteric ischaemia may also present with abdominal pain.

A careful history may elicit drugs that may result in malabsorption including cholestyramine, neomycin, colchicine and cathartics. The history should also be directed towards identifying systemic disorders that may be associated with malabsorption, including AIDS, scleroderma, thyrotoxicosis or diabetes mellitus.

Investigations

The nature and order of investigations carried out is dependent on the history. In many instances a cause will be suggested and investigations can be targeted. For example, upper abdominal pain may suggest pancreatitis, directing investigations towards demonstrating pancreatic disease. Crampy lower abdominal pain and diarrhoea would lead investigations towards exclusion of Crohn’s disease. Specific investigations are set out below.

A plain abdominal x-ray may show pancreatic calcification, which establishes the diagnosis of chronic pancreatitis. An abdominal CT scan is more sensitive in documenting calcification and may show a dilated pancreatic duct or pancreatic mass.

Endoscopic retrograde cholangiopancreatography will document changes of chronic pancreatitis with dilated and/or irregular ducts. A magnetic resonance pancreatogram is less invasive and may also document typical pancreatic duct changes.

An endoscopic ultrasound can detect chronic pancreatic disease with changes categorised as parenchymal and ductal. Parenchymal changes include increased lobulation and the presence of calcification whereas the ductal changes include dilated ducts, hyperechoic ductal margins and prominent branch ducts.

It is important to note that structural changes seen on imaging do not necessarily translate to pancreatic insufficiency since individuals with a lot of changes on imaging may have no insufficiency, and the reverse also is true.

Direct tube tests such as the secretin stimulation test remain the ‘gold standard’ for the assessment of exocrine function, but are seldom used today. They involve placement of a tube into the second part of the duodenum, the administration of secretin or cholecystokinin and the measurement of bicarbonate or enzymes in the aspirated duodenal juice. These tests are expensive to perform and uncomfortable for the patient, and may yield false positive results if duodenal collection of juice is inadequate. Alternative non-invasive tests for pancreatic function have been developed and include the bentiromide test, the pancreolauryl test, the faecal chymotrypsin assay and the faecal elastase assay. None of these tests has achieved sufficient sensitivity or specificity to attract widespread use, but this is a developing area.

In children with malabsorption, a sweat test is required to exclude cystic fibrosis.

If small bowel disease is suspected, a small bowel biopsy at upper endoscopy is usually performed in a patient with unexplained malabsorption. This may be preceded by serological tests for coeliac disease (see later). In addition to the diagnosis of coeliac disease (a common cause of malabsorption), rare causes of malabsorption such as lymphangiectasia and Whipple’s disease can also be detected. Giardia lamblia trophozoites may sometimes be visible on routine histology and a disaccharidase assay can be performed.

Barium studies of the small bowel may define defects that give rise to malabsorption, such as strictures, diverticula or fistulae. Small bowel endoscopy or wireless capsule endoscopy can be useful in difficult cases.

Small bowel bacterial overgrowth can be reliably detected only by the measurement of viable counts of bacteria in fasting proximal small intestinal aspirates obtained at upper endoscopy. This requires small intestinal intubation as well as a specialist unit experienced in anaerobic bacterial culture. The presence of an elevated serum folate and a reduced B₁₂ is a laboratory clue to bacterial overgrowth since bacteria produce folate and utilise B₁₂.

A variety of indirect tests have evolved for the diagnosis of small bowel bacteria overgrowth. These include the ¹⁴C glycocholate test, which relies upon bacterial deconjugation of bile acid and an increase in ¹⁴CO₂. This test has a high false-positive and false-negative rate.

The ¹⁴C-D-xylose breath test relies upon bacterial metabolism of ¹⁴C-D-xylose by bacteria in the proximal small intestine. ¹⁴CO₂ is formed, and is then absorbed and excreted in the breath. Although some reports suggest that this test has a high sensitivity and specificity, others have been unable to substantiate this claim. This test’s role in the investigation of small intestinal bacterial overgrowth remains unclear.

Other indirect tests, including the lactulose breath test, glucose breath hydrogen test and rice breath hydrogen test, all have unacceptable sensitivity and specificity levels.

Ileal absorptive function can be determined by Schilling’s test performed with intrinsic factor in three stages (without intrinsic factor, with intrinsic factor and after a course of treatment), or with a SeHCAT (Se-labelled homocholic acid taurine) test. Vitamin B₁₂ and bile acids are absorbed in the terminal ileum. The Schilling test is frequently abnormal with and without intrinsic factor in terminal ileal disease. Vitamin B₁₂ absorption in pernicious anaemia corrects with intrinsic factor. SeHCAT is the taurine conjugate of a synthetic bile acid and the test includes measurement of body Se retention after the administration of SeHCAT. Retention of less than 50% after 3 days suggests bile acid malabsorption.

Disorders that may Cause Chronic Diarrhoea or Malabsorption

Coeliac disease

Coeliac disease (gluten-sensitive enteropathy) is a disorder of the small intestine caused by sensitivity to gluten, a protein component of cereals found in wheat, rye, barley, triticale and possibly oats. Exposure to gluten causes small bowel damage characterised by inflammation and villous trophy.

Aetiology

The current understanding of the aetiology of coeliac disease is that gluten triggers mucosal damage due to an immune response in genetically predisposed individuals. Virtually all those affected are HLA-DQ2 or DQ8 positive. With increased screening it is now considered that the prevalence of the disease is one in 100 but only 10–15% are diagnosed—the so-called tip of the iceberg. There is 70% concordance rate in twins and a 10–15% prevalence rate in first-degree relatives. Non-HLA genes as well as other environmental factors may be involved in the development of the disease since not all HLA DQ2 and DQ8 carriers develop the disease.

Clinical features

Individuals with coeliac disease may present with classical malabsorptive symptoms of steatorrhoea: pale bulky stools, crampy abdominal pain, abdominal distension and weight loss. Growth failure or failure to thrive in children is also common.

In adults, symptoms may be much more subtle: abdominal bloating, occasional diarrhoea or nutrient deficiencies. Other presentations include infertility, miscarriage, mouth ulcers, osteoporosis or unexplained anaemia. With the availability of serological screening programmes, many individuals have been diagnosed who are asymptomatic. Iron deficiency anaemia is common and combined iron and folate deficiency is typical of coeliac disease. Bruising due to vitamin K deficiency or tetany due to vitamin D deficiency and hypocalcaemia may be the presenting features.

Dermatitis herpetiformis (see Fig 14.3) presents with a pruritic papulovesicular rash on extensor surfaces of the limbs and also on the buttocks. Small bowel changes of coeliac disease are usual, but may be patchy. The condition responds to a gluten-free diet.

Diagnosis

The diagnosis of coeliac disease is made by documenting the typical mucosal changes (Fig 14.4) on small bowel biopsies, which are usually obtained at endoscopy. Multiple biopsies should be obtained from the second part of the duodenum. It is important to ensure that the patient is on a gluten diet before performing a biopsy, otherwise an adequate challenge of gluten (the equivalent of four slices of bread per day for 4–6 weeks) should be administered and the development of positive serology checked before performing a biopsy. Small bowel biopsies do, however, have their limitations (see Box 14.3).

Figure 14.4 Subtotal villous atrophy showing total absence of villi and a corresponding increase in depth of the crypts, producing an apparently increased mucosal thickness.

Illustration based on photomicrograph from Misiewicz JJ, Bantrum CI, Cotton PB, et al. Slide atlas of gastroenterology. London: Gower Medical Publishing; 1985, with permission.