An unknown disease

Intestinal pseudo-obstruction is the name given to a relatively unknown group of disorders that cause impaired gastrointestinal motility. Normally, co-ordinated so called peristaltic contractions of the stomach and the intestines transport ingested food along the gut. In pseudo-obstruction the co-ordination of such muscular contractions is partially or completely lost. This results in impaired or blocked passage through the gut. Uncoordinated motor activity leads to impaired digestion of food and impaired absorption of nutrients. The disorder is often accompanied by bacterial overgrowth in the small intestine which further advances malabsorption.

Abdominal pain is the most common symptom
Recurrent and severe abdominal pain is the most common symptom in adult patients with intestinal pseudo-obstruction. The cause of pain is not well understood. When passage through the gut is blocked, reflex mechanisms in the nervous system of the gut cause an increase in muscular activity which may give rise to painful cramps. Muscular cramps may impair the blood circulation to the gut possibly leading to ischaemic pain. Another cause of pain is that the disease affects the nerve cells of the gut and the dying neurones may signal pain. Symptoms in pseudo-obstruction may mimic those in patients with a mechanical obstruction and the similarity to mechanical obstruction has also given the disease its name. In addition to pain, nausea, vomiting and pronounced distension are also common in pseudo-obstruction.

Intestinal pseudo-obstruction may affect parts of, or the entire gastrointestinal tract from the oesophagus to the rectum. Nausea and vomiting dominate the clinical picture if the disorder is mainly in the upper part of the gastrointestinal tract. If the lower parts are more involved the most common complaints are constipation, distension, and abdominal pain and if the disease is more widespread or mainly in the small intestine then abdominal pain, distension, vomiting and a feeling of obstruction to flow along the gut are commonly reported.

Different types of pseudo-obstruction
The most common type of pseudo-obstruction is caused by damage to the nerve cells in the bowel wall, the enteric nervous system. The bowel wall consists of several different layers. One outer longitudinal muscle layer which shortens the gut when contracted, and an inner circular layer which causes narrowing of the gut when contracted. The inside of the bowel wall is covered by the mucosa. The enteric nervous system is mainly located between the two muscle layers where it controls and co-ordinates the work of the muscle cells. Damage to the nerves here is called visceral neuropathy and the type of pseudo-obstruction which follows from such damage is termed neuropathic pseudo-obstruction.

Another type of pseudo-obstruction is caused by damage to the muscles of the bowel wall. Damage to the muscle cells is called visceral myopathy and leads to myopathic pseudo-obstruction. Visceral myopathy causes weakening of the muscular contractions. Sometimes visceral myopathy can present as long-standing cramps in the muscles of the gut.

Hereditary forms exist in both neuropathic and myopathic pseudo-obstruction. In many cases the disease may become manifest already at an early age but in others the first symptoms may not appear until adult age. In the majority of adult cases there is no family history of pseudo-obstruction and these are therefore referred to as sporadic or idiopathic cases. Secondary pseudo-obstruction may occur as a complication to other diseases. The most common form of secondary pseudo-obstruction is caused by a neuropathy that may complicate insulin-dependent diabetes mellitus. Familial amyloidosis, in Sweden known as the Skellefteå Disease, causes myopathic pseudo-obstruction and a number of so called connective tissue diseases as scleroderma or SLE can give rise to both myopathic and neuropathic pseudo-obstruction.

Difficult route to diagnosis
The onset of pseudo-obstruction is usually insidious. Acute onset is rare except in acute forms of pseudo-obstruction like Ogilvie's syndrome. Once the symptoms bring the patient to the doctor, this can be the beginning of a long and winding road to the correct diagnosis. Abdominal complaints are the third most common cause for seeking medical advice. Only upper respiratory tract symptoms and muscle and joint problems are more common. Like most gastrointestinal diseases, pseudo-obstruction cannot be recognised from the outside of the patient. Blood tests are usually normal and even an extensive investigation including ultrasonography, computed tomography, gastroscopy, barium meal, barium enema and colonoscopy may yield normal results. Dilated bowel loops can be seen in some patients, usually with advanced myopathic pseudo-obstruction.

Often the conclusion from such an investigation is that the patient suffers from a functional bowel disorder such as the irritable bowel syndrome. Although it is correct that gastrointestinal function is disturbed in patients with pseudo-obstruction, it is incorrect to conclude that the patient suffers from a much less serious condition. The risk is that patients become neglected and viewed as suffering from a comparatively harmless disorder not requiring further treatment or evaluation.

The diagnosis of pseudo-obstruction in adults rests mainly upon three techniques: symptom evaluation, pressure measurement in the gastrointestinal tract, and microscopic examination of the bowel. It is often difficult to separate pseudo-obstruction from other gastrointestinal diseases on the basis of symptoms. The most important point is perhaps to conceive at all the possibility of pseudo-obstruction. Repeated admissions for suspected bowel obstruction is usually a good reason for suspecting pseudo-obstruction and so are episodic vomiting, the feeling of standstill in the gastrointestinal tract, and severe episodes of distension. Disease mainly affecting the large bowel may present as severe constipation and therefore pseudo-obstruction should be considered also in patients with chronic constipation.

Gastrointestinal pressure measurement

Figure 1. Normal antroduodenal manometry. The arrows point at two so called activity fronts during fasting motility. After the meal the motility pattern changes into fed motor activtiy im both the stomach and the small bowel.

The muscular activity of the gut can be investigated by measuring the intra-luminal pressure, so called manometry, in the stomach and the small bowel. A specially constructed tube, a manometry catheter, is passed through the nose, via the oesophagus and the stomach into the small intestine. Electronic transducers along the catheter give information to a computer about changes in the pressure. By measuring at different levels at the same time it is possible to determine if contractions are co-ordinated and propagated along the gut (Figure 1). In typical cases of pseudo-obstruction the contractile activity is disorganised with longer or shorter bursts of uncoordinated activity (Figure 2). Intestinal manometry requires advanced technical equipment and the method is therefore available only in specialised centres. In Sweden intestinal manometry is available at Huddinge University Hospital and Karolinska Hospital in Stockholm, Sahlgren's University Hospital in Gothenburg. More recently the Academic Hospital in Uppsala and Trelleborg Hospital have also taken up this technique.

Figure 2. Abnormal antroduodenal manometry. The arrows point at so called "bursts" of uncoordinated phasic activity, which is typical of neuropathic pseudo-obstruction.

Microscopic examination of the bowel wall
The final proof of organic disease in muscles and nerves of the gut comes from histopathologic examination of bowel tissue. Superficial biopsies that can be taken at endoscopy usually only include the mucosa and such biopsies are insufficient for evaluation of pseudo-obstruction. Both nerves and muscles are located deep into the bowel wall, hence the biopsy has to cover all layers of the bowel wall. A special technique that utilises laparoscopic surgery for full thickness biopsy of the bowel has been developed at Huddinge University Hospital. Both electron microscopy and light microscopy with special stains are used in the investigation of bowel biopsies. Thus, even minor changes in nerves or muscle cells can be detected.

Treatment
There is today no curative treatment for pseudo-obstruction. The disease is usually chronic and it does not resolve with time. Often the severity of the disease may vary with time so that episodes with few or no symptoms and good function can occur between periods of more severe symptoms. In others the disease may have a more chronic course with symptoms more or less daily. Abdominal symptoms, in particular pain, and malnutrition are the two most difficult problems for the patient with pseudo-obstruction. The aims of therapy are symptom relief and nutritional support.

Analgesics - a double-edged weapon
Visceral pain, that is pain that comes from viscera like the intestines, is difficult to treat. The mechanisms behind the pain in pseudo-obstruction are not well understood and this makes it difficult to find an effective and durable pain killer. Opioid analgesics, although effective in the short term for pain, usually lead to further deterioration of intestinal motility and may give rise to a vicious circle: deterioration of motility leads to more symptoms, which in turn leads to more analgesics and further deterioration of motility.

Despite the obvious disadvantage of these drugs it is sometimes necessary to use them, even for longer times because no other option is available to treat the pain. The use of morphine or any other opioid should always be carried out in consultation with specialists in analgesia.

Another way to relieve symptoms is to improve the gastrointestinal motor function in pseudo-obstruction. Several new drugs, so called pro-kinetics, have been developed and some of them like cisapride (Propulsid (R), Prepulsid (R)) seems to have a beneficial effect in certain types of pseudo-obstruction. Other drugs with a potential for symptom relief in pseudo-obstruction are those that mimic the effects of some of the hormones that normally are produced by the stomach and the intestines. Drugs with a direct effect on muscle tone have a potential for relieving long-standing cramps in the gut.

More effective treatment is available for other symptoms in pseudo-obstruction. Nausea and vomiting can be treated effectively with modern antiemetics. Heartburn and acid regurgitation that often trouble the patient with pseudo-obstruction usually respond well to acid reducing drugs like the new proton pump inhibitors. Constipation can be treated with stool softeners and bulking agents of the same kind as those given for functional constipation.

Surgical treatment
Many patients with pseudo-obstruction have been operated on more than once to rule out a mechanical obstruction. Surgery has a limited role for the alleviation of symptoms in pseudo-obstruction. Surgery may even make patients worse. The most successful outcome of surgery is achieved when a specific and well-defined problem can be addressed like myotomy in achalasia or colectomy in severe slow transit constipation. In selected cases it can become necessary to remove a non-functioning segment of the gut if its presence repeatedly gives rise to complications. The experience with intestinal diversion, such as ileostomy, without resection has been disappointing.

Nutrition
Malnutrition is a common problem in pseudo-obstruction. Oral nutrition should be maintained as far as possible. The normal digestion depends on the motor function of the gut. Ingestion of food stimulates gastrointestinal motility. In pseudo-obstruction the response to food is often inappropriate and eating can provoke symptoms by inducing hyperactivity and cramps in the intestines. The motor response seems to differ with the type of food that has been ingested. Fibre-free food requires little motility and fully absorbable food requires hardly any motor activity of the gut. Changes in the diet can lead to improvement of symptoms and the nutritional status.

Patients with disease mainly in the upper parts of the gastrointestinal tract can receive nutrition with the help of a small tube which is inserted through the nose via the oesophagus and the stomach to the proximal parts of the small intestine. This is called tube feeding or enteral (enteral = with the help of the intestines) feeding. Parenteral nutrition (nutrients given as an intravenous infusion) is sometimes necessary in severe cases of pseudo-obstruction. This mode of treatment carries a higher risk for complications such as septicaemia and thrombosis.

Bowel transplantation
Recent advances in organ transplantation have made it possible to replace a non-functioning bowel with bowel from another person. Bowel transplantation is still under development and although promising results have been achieved in children with pseudo-obstruction, it is today too early to determine if transplantation can become a valid option for patients with pseudo-obstruction.

General

An unknown disease

Scientific