EDS/JHS & CIPO – Professor Qasim Aziz & Dr Asma Fikree

Identification of CIPO subgroups with underlying connective tissue disorders, and the assessment of GI anatomy, motility and response to pharmacology in CIPO subjects using novel MRI techniques.

Applicant: Dr Asma Fikree

Co-applicant: Professor Qasim Aziz

What is CIPO?

Chronic intestinal pseudo-obstruction (CIPO) is a disorder of the gut that affects the movement of contents through the intestinal tract. Although it usually affects the small and large intestine, some people experience difficulties linked to their oesophagus (gullet) and/or stomach. The expression ‘pseudo-obstruction’ is used to describe the disorder because patients have symptoms usually associated with an obstruction somewhere in the digestive tract and yet no physical obstruction is present.

What are the consequences of CIPO?

Although it is rare, it can be life threatening and affects children as well as adults. Children/adults with CIPO are not able to eat normally because of symptoms that include abdominal pain, abdominal bloating (which can be so severe that affected individuals can look pregnant), nausea, high volume vomiting, and severe constipation. This has numerous consequences including malnutrition, either because the gut is unable to absorb sufficient nutrients or because the symptoms restrict affected individuals from eating normally. CIPO can cause severe and chronic pain that is very difficult to treat effectively and can occur repeatedly. This can lead to multiple ineffective operations to attempt to ‘unblock’ the bowel or can lead to treatment with very high doses of opiate painkillers (e.g. morphine) which unfortunately can cause a further deterioration in the movement of the bowel and therefore worsen the problem.

What causes CIPO?

The condition can be primary (with no known cause), or can occur secondary to some systemic disease or cancer. Recently it has been noted that a large proportion of patients with CIPO have an underlying connective tissue disorder. Connective tissue is one of the building blocks of the body. It serves as scaffolding to support and enclose the tissues and organs of the body, including the digestive tract. In connective tissue disorders, disruption of connective tissue leads to multiple symptoms and problems throughout the body, including the GI tract.

JHS and GI problems

The Joint Hypermobility Syndrome (JHS) is an inherited connective tissue disorder characterized by very flexible joints, joint pain and very stretchy and elastic skin. It is also known as Ehlers Danlos Syndrome Hypermobility Type (or Type III). It is very common and affects up to 1 in 4 people, albeit to varying degrees. Recently published work by our group has shown that there is a strong link between the JHS and GI symptoms, particularly with constipation, abdominal pain and bloating, all of which are common in CIPO. Furthermore, anecdotal evidence from GI clinics has revealed that several adult and paediatric patients presenting to GI clinics with CIPO have underlying JHS. As yet, it is unknown what percentage of patients with CIPO suffer with the JHS and whether they have similar or different characteristics and prognosis to other CIPO patients without Joint Hypermobility.

Diagnosis of CIPO

Diagnosis of CIPO requires the presence of distended non-functioning bowel and/or the presence of abnormal movement of the bowel in the presence of typical (obstructive) symptoms.  Distension of the bowel can be detected using x-rays, and abnormal movement can be detected using physiological assessment (with tubes inserted via the nose and fed into the small bowel). Both methods have their drawbacks – x-rays involve radiation and physiological assessment is very invasive and uncomfortable. As such, it is not uncommon for patients with suspected CIPO to have only one of the above two diagnostic tests, which is suboptimal. The ideal test for CIPO would be one which is non-invasive, involving no radiation and which could detect both movement and distension of the bowel.

Treatment of CIPO

There is no uniformly effective treatment strategy for patients with CIPO. Patients are generally passed from one specialist to another, each attempting to address isolated aspects of the disease rather than adopting a more holistic approach. Regrettably, with the passage of time such patients may undergo numerous invasive and unnecessary investigations or ill-advised, ineffective and occasionally damaging treatments all of which have serious consequences. This includes  dependence on and addiction to drugs (opiates) for severe chronic abdominal pain,  malnutrition due to the inability to eat normally, with an occasional need to turn to intravenous feeding, and  severe depression with some patients resorting to suicide. In severe cases patients with intractable symptoms can proceed to having either their bowel removed or replaced (intestinal transplant), both of which have long term consequences and can worsen quality of life.

Proposed research aims in CIPO

Clearly there is a need for good quality research in CIPO and we have identified 3 main areas for research which would be relevant to patients

  1. First and foremost it is important to identify if there any  common subgroups of patients with CIPO , who can be identified clinically. As there are numerous causes of CIPO, many of which are extremely rare, it would be important to focus research efforts on the more common subgroups first. One potential area would be the group of patients with the connective tissue disorders, such as the JHS.
  2. Second, it would be advantageous to identify a robust diagnostic technique which would enable the assessment of both the distension and movement of (different parts of) the bowel.
  3. Third, it would be useful to have a tool to assess the response of the gut to drugs , so as to test which medications will lead to an improvement in gut function.

Study 1- Association between CIPO and JHS

We would like to determine what proportion of patients with CIPO have the JHS and what their characteristics are e.g. symptoms, response to medications, other associated problems such as pain and problems with feeding. It would also be interesting to determine whether in this group of patients, there is a family history of CIPO. Discovering the strength and importance of the link between CIPO and the JHS may help us identify and categorise a subgroup of patients with CIPO who also have a connective tissue problem and this may help us specific treatment for these patients.

To do this we plan to examine all CIPO patients for the JHS, and to obtain detailed information on their gastrointestinal and non-gastrointestinal symptoms as well as their family history. We would combine this information with what we know of their bowel movement and distension to build up a clearer picture of whether this subgroup of CIPO patients is common (and therefore worth researching) and whether they have a particular presentation.

Study 2: MRI assessment of bowel anatomy and movement

MRI is an emerging tool for assessment of bowel structure and function. It has numerous advantages including the fact that it does not involve radiation and is non-invasive. Emerging techniques in MRI, being pioneered at University College Hospital (UCH) enable detailed assessment of the movement of different parts of the gut in real time, as well as the distention of different parts of the gut. Hence this diagnostic tool will enable assessment of both movement and distension of the gut without causing discomfort to the patient. Through collaborations that we have formed with UCH, we plan to carry out MRI scanning of patients with CIPO to determine exactly what is happening in their gut and how that correlates to the symptoms they experience. Such data has never been collected in real time before so this novel information would greatly improve our understanding of these patients. Furthermore, by comparing subgroups of CIPO patients e.g. those with and without JHS, we can determine what differences there are in the movement and structure of the bowel in these different groups. This will potentially have implications for the management and treatment of these different groups of CIPO patients.

Study 3: MRI as a tool to assess the clinical and physiological response of CIPO patients to potential treatments

Possibly the most important question we would like to address is how different drugs work on the gut in CIPO, how they change the movement of the gut and how this relates to symptoms. Once again, we hope to use MRI to assess this, as movement of the gut can be assessed in real time and drugs can be administered when the patient is in the MRI scanner. Neostigmine is a drug which is often used in CIPO to improve gut movement. Work done on healthy volunteers at UCH has shown that administration of neostigmine to healthy volunteers improves gut movement and function. We would like to repeat this study in patients with CIPO to determine how the gut movement changes with neostigmine and whether this is associated with an improvement in symptoms. The same technique can be used to assess the gut’s response to other newer drugs. In this way we hope to identify a range of drugs which results in a symptomatic and physiological improvement in CIPO.

Expected outcomes:

With these 3 studies we hope to achieve the following:

1-To determine if JHS is common in CIPO and if it is clinically relevant, particularly in familial cases of CIPO. We would also like to determine how the quality of life differs in CIPO patients with vs without JHS.

2- We would like to establish MRI as a gold standard for diagnosing, characterising, and categorising CIPO and for furthering our understanding of the range and severity of motility problems in these disorders.

3-To establish MRI as a tool to identify medications which result in a clinical and physiological improvement in CIPO patients.

Resources needed:

Through our newly developed collaboration with the UCH radiology department we have access to MRI scanners and have funding to perform the scanning. However we will need funding for a research nurse (for 2 years) who will be required to help carry out the project. The research nurse will be required to attend clinics to help identify appropriate CIPO patients and recruit them to the various studies, carry out hypermobility assessments, organise scanning slots, help run the studies, and carry out the administrative research tasks. He/she will also help identify CIPO patients attending surgical or other clinics, and will be able to help recruit patients from other sites.

The nurse will have other duties both clinical and research and these would include:

Providing phone/helpline support to these CIPO patients  before/after their clinic appointments.

Entering CIPO patients prospectively onto the GINMD database that PORT have funded

Liaising with GOSH to help enter the paediatric data onto the GINMD database

Liaising with other centres in the UK which have previously expressed an interest in being involved with the CIPO database, and helping those sites access and enter their patients onto the database.

Funding required:

Research nurse :£42,134 per year for 2 years.

We would like to ask PORT to fund the first year– total £42,134