BMJ Learning

Chronic diarrhoea

د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Key points

The main causes of chronic diarrhoea in the Western world are, in order of frequency:
• Irritable bowel syndrome
• Lactose intolerance
• Coeliac disease
• Small bowel infection, including giardiasis and bacterial overgrowth
• Inflammatory bowel disease.
Most patients with chronic diarrhoea have irritable bowel syndrome, which requires a variety of approaches. These include dietary manipulation, drugs, and psychological therapy

Epidemiology

Chronic diarrhoea in adults is common. In the United Kingdom, 5.3% of men and 4.3% of women report soft mushy stools on a regular basis.
Most of these episodes will have negative investigations and be labelled as either:
Functional diarrhoea if painless
Irritable bowel syndrome with diarrhoea, if associated with abdominal pain or discomfort.


Learning bite
Functional diarrhoea has been classified separately from irritable bowel syndrome in a consensus statement (Rome III). The statement defines it as the continuous or recurrent passage of loose (mushy) or watery stools without abdominal pain or discomfort.

Epidemiology of specific conditions

Irritable bowel syndrome
The prevalence of patients with diarrhoea and abdominal pain meeting the Rome I criteria for irritable bowel syndrome may be as high as 4 in 100 in the UK. The prevalence is similar in both industrialised and tropical populations.
There is a strong female predominance of irritable bowel syndrome in those seeking medical care. This in part reflects the reluctance of young men to consult a doctor since, in community surveys, there is much less of a sex difference in prevalence.

Adult acquired hypolactasia

Lactose malabsorption, due to hypolactasia developing after weaning, is the norm worldwide. The lactase enzyme is needed to hydrolyse the disaccharide lactose to the mono-saccharides glucose and galactose, which can then be absorbed.
Adult acquired hypolactasia is due to a genetically determined "switch off" of the synthesis of the lactase enzyme in the small intestinal enterocyte brush border.

There is a mutation, T/C (-13910), which prevents this normal post-weaning switch off, leading to persistence of lactase production into adult life. The mutation arose in north western Europe and has spread southward and eastward, so that racial origin is now a strong predictor of adult acquired hypolactasia - the prevalence being lowest in north west Europeans (10%), 40% in southern Mediterranean and Middle Eastern patients, and up to 90% in patients from the Orient. A separate mutation appears to account for lactose persistence in Africa.

Coeliac disease

Coeliac disease has a prevalence which varies from around 1 in 1000 in the USA to 1 in 100 in the UK. Although many patients with coeliac disease are diagnosed in early childhood, about half are diagnosed in adulthood, and a few are diagnosed in their seventh decade. The genetic predisposition to develop coeliac disease exists in a third of the population, so evidently some additional environmental factor is also required.

Giardiasis

Chronic giardiasis is more common in people who have lived in the tropics. However, it is also seen in those who have never left temperate zones but have been exposed to contaminated ground water - for example backpackers and campers.

Crohn's disease, ulcerative colitis, and microscopic colitis

Crohn's disease and ulcerative colitis have prevalence in Europe of around 14 and 24 per 10 000 respectively. They commonly affect people in their teens and early adulthood. This distinguishes them from microscopic colitis; a rarer condition largely of elderly people, in whom the prevalence is 2 per 10 000.
Small intestinal bacterial overgrowth
often secondary to achlorhydria, affects up to 15% of elderly people. In most patients it appears to cause few symptoms.


Causes of chronic diarrhoea
The common causes of chronic diarrhoea in adults, listed by order of frequency, are:
• Irritable bowel syndrome with diarrhoea or functional diarrhoea
• Dietary intolerances, for example, acquired hypolactasia, wheat intolerance, and, rarely, food allergies
• Coeliac disease
• Crohn's disease
• Ulcerative colitis
• Microscopic colitis
• Small bowel infection

Small bowel infection

Giardiasis
Small intestinal bacterial overgrowth:
Can be secondary to achlorhydria when the bacteria are mostly pharyngeal commensals and cause few symptoms
Can be due to diverticula, dysmotility, or post-surgical blind loops when the bacteria are often colonic in type, for example, Escherichia coli, causing symptoms of malabsorption
Is also a feature of patients with subacute intestinal obstruction secondary to radiation or previous surgery

Tropical sprue

Chronic pancreatic insufficiency, pancreatic cancer, and cystic fibrosis Pancreatic insufficiency is usually secondary to alcohol abuse. A rare, steroid responsive, autoimmune chronic pancreatitis is now being recognised more frequently
Bile salt malabsorption
This is a relatively rare condition, but you should suspect it in those in whom chronic diarrhoea develops suddenly
Radiation enteritis
Neoplasia: cancer of the colon, intestinal lymphoma


Miscellaneous
Drugs and alcohol
Metabolic disorders (hyperthyroidism, diabetes)
Neuroendocrine tumours (carcinoid, gastrinomas, VIPomas)
Mesenteric ischaemia (rare)
Autonomic neuropathy
Abetalipoproteinaemia
Intestinal lymphangiectasia
Whipple's disease.

Learning bite

Many people recognise that certain foods cause diarrhoea and they avoid these foods and hence do not consult a doctor. However, unrecognised dietary intolerances are a common cause of chronic diarrhoea.

Clinical features

Patients with chronic diarrhoea can present with the following symptoms:
Abdominal pain
Weight loss
Vomiting
Steatorrhoea and abdominal distension
Blood in the stool
Minor outlet bleeding - bright red blood on the toilet paper.


Abdominal pain
While all conditions causing chronic diarrhoea can cause abdominal discomfort, the presence of severe and disabling pain is most commonly due to the irritable bowel syndrome. Typically, the episodes of pain occur in clusters, with days of freedom from the pain. The pain is often colicky and may be relieved by defecation. Eating certain foods and stress may precipitate it.
The other conditions that cause abdominal pain with diarrhoea are Crohn's disease, chronic pancreatitis, and pancreatic cancer.
In other disorders causing chronic diarrhoea, patients experience low grade discomfort, often with bloating and some relief by defecation which can be confused with irritable bowel syndrome.

Weight loss

Weight loss is a prominent feature in Crohn's disease, chronic pancreatitis, and pancreatic cancer. Patients with irritable bowel syndrome or functional diarrhoea do not usually lose weight.
Patients with malabsorption usually lose weight because they try to avoid symptoms by eating less. In contrast, patients with chronic pancreatitis lose weight despite increasing their intake. Glycosuria is also a frequent finding in such patients, who can develop both pancreatic exocrine and endocrine insufficiency. The natural history for painful pancreatitis is for the pain to be worse at the start of the disease and to gradually decline, particularly in those who stop drinking alcohol.

Bloody diarrhoea

Bloody diarrhoea with blood mixed in the stool suggests ulcerative colitis or Crohn's disease, more rarely this may be due to colon cancer.
Acute onset of diarrhoea with vomiting
When acute diarrhoea and vomiting typical of acute gastroenteritis fails to resolve and the patient is left with chronic diarrhoea, this may suggest post-infective irritable bowel syndrome. This accounts for 6-17% of all patients with irritable bowel syndrome.
People with bile salt malabsorption and coeliac disease can also present in this way.

Steatorrhoea and abdominal distension

Steatorrhoea describes pale fatty stools which stick to the toilet pan and are difficult to flush away. You should suspect fat malabsorption as seen in coeliac disease, pancreatic insufficiency, giardiasis, and small intestinal bacterial overgrowth.
Small intestinal bacterial overgrowth is most commonly due to duodenal or jejunal diverticulosis. These are usually seen in elderly patients, who may present with steatorrhoea and abdominal distension.

While coeliac disease used to only be diagnosed when associated with steatorrhoea, nowadays easy screening with endomysial or tissue transglutaminase antibody tests mean that it is usually detected before fat malabsorption becomes obvious.
Coeliac disease classically presents with weight loss and diarrhoea - patients often also have anaemia and hypocalcaemia.


Minor outlet bleeding
Minor outlet bleeding is rectal bleeding characterised by blood on the toilet paper rather than mixed with the stool often associated with painful defecation. Although this is common in all causes of diarrhoea , in such patients you need to exclude inflammatory bowel disease and cancer of the colon, particularly in those who are over 50 years and have a recent onset of symptoms.

Patterns of diarrhoea

Urgency
All diarrhoeal conditions can cause urgency, with stools that are typically soft and poorly formed.
Nocturnal symptoms
Diarrhoea due to irritable bowel syndrome and functional diarrhoea rarely wakes the patient from sleep, which usefully distinguishes them from the other disorders which may do so. Diabetic diarrhoea and that due to bile salt malabsorption typically cause nocturnal diarrhoea.

Specific features

Before diagnosing irritable bowel syndrome, you should look for the following alarm symptoms which should prompt careful evaluation of alternative diagnoses:
• Age more than 50 years
• Short history of symptoms
• Documented weight loss
• Nocturnal symptoms
• Male sex
• Family history of colon cancer
• Anaemia
• Rectal bleeding
• Recent antibiotic use.


Approach to the patient
If you take a careful history, it may become clear that the diarrhoea is due to drugs or past treatments. For example, if you elicit that a patient had radiotherapy for cervical cancer and has resulting radiation enteritis, or that the diarrhoea began with the commencement of a drug such as metformin, this will save you doing many fruitless investigations.

Dietary history

While most patients will work out for themselves if certain foods cause diarrhoea, it is still worth asking about dietary habits, particularly whether there have been any changes which coincide with the onset of diarrhoea.

• Fructose - this is poorly absorbed. It is found in apples, oranges, grapes, pears, concentrated fruit juices, and diabetic drinks
• Sorbitol - this is virtually unabsorbable. It is found in pears, plums, and apples
• Mannitol - this is unabsorbed. It is found in sugar-free chewing gum, mints, and medicinal syrups
• Caffeine - this stimulates colonic motility
• Vegetables and wheat - wheat, onions, leeks, and some root vegetables such as artichokes contain substantial amounts of poorly absorbed sugars (including oligofructans such as inulin and raffinose as well as scodarose and stachyose).
It is worthwhile asking about excessive intake of the following as they can all cause chronic diarrhoea:

The most common source of dietary fibre in the UK diet is wheat, of which around 10% escapes absorption in the small intestine and enters the colon. Products containing wheat include bread, biscuits, cakes, cereals, and pasta, so it is worth enquiring about daily intake. You should ask particularly whether these products are made from wholemeal flour.

Past medical history

A history of multiple medically unexplained non-gastrointestinal complaints as well as bowel specific symptoms is a common feature of irritable bowel syndrome reflecting widespread symptom anxiety. This should not discourage you from performing a thorough evaluation, but recognising this may enable you to avoid excessive unnecessary investigations.

Drugs

Drugs that can be associated with diarrhoea include:
• Proton pump inhibitors such as omeprazole
• Selective serotonin reuptake inhibitors
• Angiotensin converting enzyme inhibitors
• Beta blockers
• Statins
• Metformin
• Mefenamic acid.
You should pay particular note to recent antibiotic use since the incidence of Clostridium difficile is increasing and is no longer restricted to patients admitted to hospital


Alcohol
Large volumes of beer may act as a laxative. Chronic alcohol excess is also associated with chronic pancreatitis.
Family history
Crohn's disease, ulcerative colitis, coeliac disease, irritable bowel syndrome, and colon cancer all show important genetic influences.

Examination

On examination, you should assess the nutritional status of the patient and look for evidence of weight loss.
You should examine patients for:
Anaemia
Signs of iron deficiency - ridged, pale, or spoon shaped nails
Clubbing - seen in Crohn's ileitis
Signs of thyrotoxicosis.

Psychological examination

Psychological examination aided by simple questionnaires such as the Hospital Anxiety and Depression Scale or the Personal Health Questionnaire 15 may be of value in irritable bowel syndrome, particularly if it indicates somatisation or marked anxiety.

Examination of the abdomen

Look for scars of previous surgery. These may give you a clue to the diagnosis of subacute intestinal obstruction, secondary adhesions, or small intestinal bacterial overgrowth due to a surgical blind loop. You should also look for radiation dermatitis, indicating previous radiotherapy.
Most conditions causing malabsorption yield no abnormal physical signs in the abdomen. If malabsorption persists for years, it may lead to hypoalbuminaemia causing peripheral oedema, iron deficiency with brittle spoon shaped nails, and osteomalacia with bone deformity. Tenderness over the sigmoid loop on deep palpation may be a feature of irritable bowel syndrome.

Patients with Crohn's disease may have matted loops of ileum causing a palpable abdominal mass, usually in the right iliac fossa. Sigmoidoscopy may be valuable in indicating the presence of pale stool indicative of steatorrhoea or inflammatory bowel disease, especially ulcerative colitis, in which the rectum is usually inflamed.


Investigations
Blood tests
Full blood count, serum ferritin, serum B-12, red cell folate Malabsorption commonly causes anaemia, usually due to iron, B-12, or folate deficiency
Urea and electrolytes
Albumin, and liver function tests.Calcium
Hypocalcaemia is usually due to malabsorption of vitamin D.Fasting blood sugar - patients with pancreatic insufficiency and weight loss may develop endocrine insufficiency of the pancreas
Erythrocyte sedimentation rate or C reactive protein Elevated inflammatory markers .

Serological tests

Tissue transglutaminase antibodies - these have high sensitivity and specificity for coeliac disease
Helicobacter pylori antibodies - as long standing H pylori gastritis can lead to achlorhydria, which can cause small intestinal bacteria overgrowth, you should check these antibodies in elderly people with iron deficiency anaemia or small bowel bacterial overgrowth
ASCA - antibodies to Saccharomyces cerevisiae are more common in Crohn's disease than in ulcerative colitis or the general population (however these are not sensitive or specific enough to make a diagnosis).
As Giardia lamblia is a non-invasive organism, it does not result in diagnostic specific antibodies

Stool tests

Stool cultures
These are rarely helpful in chronic diarrhoea except for identifying giardiasis and amoebiasis.
Stool microscopy
Although fat in the stool can easily be recognised by microscopy, this is rarely done nowadays. The sensitivity of stool microscopy for identifying the cysts of G lamblia is around 75% for the first stool, and 85% after examination of three stools.
There is also an ELISA test to detect giardia antigen in the stool which has a sensitivity close to 100% but, unlike endoscopy, this is not widely available.Duodenal biopsy is the most reliable way of diagnosing giardiasis.


24 hour stool weight
Though rarely done except in difficult cases, a 24 hour stool weight can be helpful in distinguishing irritable bowel syndrome, in which stool weights are normal (less than 250 g), from other diarrhoeal diseases.

Further investigations

Endoscopy
If there is evidence of malabsorption, you should arrange for an endoscopy and duodenal biopsy to detect coeliac disease or tropical sprue.
Even in the absence of tissue transglutaminase antibodies, coeliac disease remains a possibility since 5% of patients with coeliac disease do not have tissue transglutaminase antibodies. Since these are usually IgA based tests it may be worth checking immunoglobulin levels to exclude IgA deficiency which is found in 1% of the population and may give a false negative result.

Duodenal biopsy is the most reliable way of diagnosing giardiasis. Numerous trophozoites, densely adherent to the duodenal mucosa, are seen under the microscope.
Examination of at least two duodenal biopsies has been shown to have a detection rate of close to 100%.
Duodenal biopsy shows patchy villous atrophy in tropical sprue.

Sigmoidoscopy

A sigmoidoscopy allows assessment of both stool and colorectal mucosa, and provides a diagnosis in the case of ulcerative colitis.
Colonoscopy
In the absence of any evidence of malabsorption, you should consider requesting a colonoscopy, particularly in elderly people, to look for inflammatory bowel disease or microscopic colitis and, in patients with new onset diarrhoea, to exclude cancer of the colon.
During the colonoscopy, diverticulae are commonly noted in elderly people, though in most situations these will not be responsible for symptoms.

Radiology

Abdominal CT
In a patient with a history of alcohol abuse who has epigastric pain radiating to the back, you should request a CT to look for pancreatic atrophy and calcification, typical of chronic pancreatitis, or a mass suggesting pancreatic cancer.
Barium follow through
Where there are signs of malabsorption, if duodenal biopsies are normal, you should consider requesting a barium follow through. This can identify Crohn's disease or structural abnormalities such as jejunal diverticulae or small bowel strictures, which can be associated with small bowel bacterial overgrowth.


Se75HCAT retention test
Bile salt malabsorption can be diagnosed by the percentage retention of Selenium75 homo-cholic acid taurine (Se75HCAT).
Se75HCAT is a gamma-emitting radio-labelled bile acid. It undergoes entero-hepatic recirculation - it is absorbed in the terminal ileum and excreted into the duodenum with bile. At seven days, retention of this radio-labelled bile acid is normally more than 15%. Patients with significant bile acid malabsorption often retain less than 5%, a level which strongly predicts a good response to bile salt binding agents like colestyramine.

Glucose breath hydrogen test and jejunal aspirates

Small intestinal bacterial overgrowth is most conveniently diagnosed using the glucose breath test. The patient drinks 50 g of glucose in 180 ml of water and then serial breath hydrogen measurements are made. A rise of greater than 20 parts per million is abnormal since all the glucose will normally be absorbed before reaching the bacteria in the colon.
The breath test is simple and well tolerated, unlike the gold standard which is jejunal aspirate with aerobic and anaerobic culture. Finding more than 105 colony forming units per ml, particularly of bacteria of colonic origin, supports the diagnosis of significant small intestinal bacterial overgrowth.

Lactose breath hydrogen test

This is the most useful way to diagnose hypolactasia. The patient drinks 50 g of lactose in 180 ml of water and breath hydrogen is monitored for three hours. A rise of over 20 parts per million indicates significant lactose malabsorption and correlates well with symptoms.
This is probably preferable to a genetic blood test or biopsy based assay. Low mucosal levels of lactase do not reliably predict symptomatic lactose malabsorption, while a positive lactose breath hydrogen test does.

Autonomic function testing

Direct testing of the gut autonomic system is difficult. It is more convenient to use standard cardiovascular tests such as response to tilt, the Valsalva manoeuvre, and R-R variability during deep breathing to test autonomic function. Abnormalities of these tests correlate reasonably well with abnormalities of the gut autonomic system.

Management

Management of specific conditions
Irritable bowel syndrome and functional diarrhoea
Dietary exclusion
Various forms of dietary exclusion have been suggested as treatments. While the occasional patient with excessive intakes of coffee, fruit, or bran may benefit, often the effect is disappointing. Wheat and dairy products are commonly advised to be excluded and, in uncontrolled trials, these have produced benefit in up to 40% of patients.
It is not known how much of this effect is due to placebo effect but the treatment is certainly safe, provided it is done under dietetic surveillance to avoid nutritional deficiencies.


Drugs
Loperamide is a useful symptomatic treatment, not only because it reduces bowel frequency but also because it gives the patient a sense of control. The fear of urgency and inconvenient defecation can often dominate a patient's life. Once they know they can control it, the fear of the symptoms subsides considerably and quality of life improves. Unfortunately although effective in treating the diarrhoea it often does not help the abdominal pain and may give an unpleasant sense of distension (bloating).

5HT3 antagonists have been shown to be moderately effective in irritable bowel syndrome, with a number needed to treat (the number of patients who need to be treated to get one more patient to improve than when given placebo treatment) of 7. Regrettably, Alosetron is not available in the UK and, although it was proved effective, its marketing has effectively ceased because of the rare (1 in 700) occurrence of ischaemic colitis.

Tricyclic antidepressants such as amitriptyline are widely used and particularly effective in irritable bowel syndrome with diarrhoea. They work best in patients who are not depressed, at low doses, when they probably act as anxiolytics rather than antidepressants. Patients also tolerate them best at low doses. Amitriptyline is particularly effective in those with irritable bowel syndrome with diarrhoea, possibly because of its anticholinergic properties.

Dietary intolerances

Once you or the patient suspect an intolerance, you should do a trial of exclusion. Unlike a true allergy, the patient can usually tolerate small amounts of the suspect food. Patients with hypolactasia may be able to continue to enjoy milk by drinking milk pre-treated with bacterial lactase enzymes.
Lactose exclusion is only relevant if patients consume more than 240 ml of milk or the equivalent amount of lactose (12 g). At doses lower than this, patients with hypolactasia do not develop more symptoms than when given a lookalike lactose-free milk.

Coeliac disease

Usually, the patient needs to adhere to a lifelong gluten-free diet since even small amounts of gluten can lead to chronic villous atrophy, which can lead to malabsorption and osteoporosis.
Chronic giardiasis
Metronidazole 800 mg eight hourly for five days is usually effective.

Dietary challenge

Although there is no evidence for this, expert opinion strongly recommends that if the patient improves after a simple trial of exclusion, you should then do a dietary challenge, reintroducing the suspect food to definitively confirm that the particular food does reproducibly induce symptoms.

Inflammatory bowel disease

Crohn's disease of the small bowel can be treated with budesonide and mesalzine using formulations designed to deliver the drug to the small bowel.
You should treat ulcerative colitis with prednisolone 30 to 40 mg or budesonide 9 mg initially, reducing the dose by 5 mg a week for prednisolone and by 3 mg every two weeks for budesonide.
If the patient promptly relapses then you should start azathioprine or mercaptopurine, which takes four to six weeks to be fully effective.


However, if the patient is sufficiently unwell, an acute response is needed. It is then necessary to give a further course of prednisolone or budesonide to suppress symptoms while awaiting the onset of the effects of azathioprine or mercaptopurine. When these drugs become fully effective, the steroids can then be weaned.

Infusions of anti-TNF antibody are usually reserved for Crohn's disease that responds poorly to the above regimen. Surgery is reserved for patients whose disease is resistant to medical therapy (see British Society of Gastroenterology inflammatory bowel disease guidelines for more details).

Microscopic colitis

This can be difficult to treat but may respond to budesonide, initially 9 mg daily tailing to 3 mg daily, with or without mesalazine. You can use loperamide to control residual symptoms.
Small intestinal bacterial overgrowth
This is a chronic relapsing condition in which the underlying cause is often irreversible. You should usually treat it with intermittent courses of antibiotics. The antibiotic with the best evidence is norfloxacin. Alternatives include metronidazole and tetracycline.

You should give antibiotics for five to 10 days only. The patient should then wait to see if their symptoms relapse. If their symptoms do relapse, you should give further antibiotics, preferably in a rotating fashion to avoid the development of drug-resistant organisms.
Those with severe underlying motility disorders, most commonly secondary to scleroderma, may benefit from prokinetics including metoclopramide, erythromycin, or octreotide, though in these rare conditions the evidence base is weak.

Tropical sprue

You should treat this with tetracycline 250 mg six hourly combined with folic acid 5 mg daily for three months. Folic acid is thought to enhance mucosal recovery.
Pancreatic insufficiency
Abstinence from alcohol is most important in patients with pancreatic insufficiency due to alcohol excess. When pancreatic insufficiency is due to autoimmune pancreatitis, it has been shown to respond to treatment with corticosteroids.

Both types will benefit from pancreatic enzyme supplements containing adequate amounts of lipase, amylase, and proteases. The patient can sprinkle them on food or take them as capsules interspersed with their meal to ensure adequate mixing with the food. The usual dose is three to four capsules with the main meal and two to three with smaller snacks.
Since these enzymes are denatured by gastric acid, anti-secretory agents such as proton pump inhibitors may improve the clinical response.

Bile salt malabsorption

This is a gratifying condition to diagnose since it responds dramatically to the bile salt binding agent colestyramine, 4 g three times daily. The response depends on the severity of malabsorption. Nearly all patients with more than 5% retention of Se75HCAT at seven days respond, while only around half of those with 5% to 10% retention respond. When retention is more than 10%, there is no worthwhile response.


Drug induced diarrhoea
In drug induced diarrhoea, it may not always be feasible to switch to an alternative drug. In such patients, it is acceptable to continue the offending drug and start loperamide or codeine for symptomatic relief.
Diabetic diarrhoea
The effects of autonomic neuropathy are difficult to reverse. Symptomatic treatment with loperamide or codeine may help.

Although many patients with coeliac disease are diagnosed in early childhood, around half are diagnosed in adulthood and a few are diagnosed in their seventh decade. Intestinal carcinoid does not cause malabsorption and is extremely rare compared with coeliac