Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is characterised
by chronic intestinal inflammation. The two major types
of IBD are Crohn's disease and ulcerative colitis, although
other less common IBD conditions are also included in this
category.
Crohn's Disease
Introduction
Crohn's disease causes inflammation of the
bowel. It most commonly affects the lower small intestine
(ileum) and the large intestine (colon), but may involve
any part of the digestive tract from the mouth to the anus.
The inflammation extends through the entire thickness of
the bowel wall. Such inflammation can cause abdominal pain,
diarrhoea and a range of other symptoms including fever
and weight loss.
The disease occurs about equally in men and
women and usually appears for the first time in patients
<30 years old with peak incidence in those aged 14-24 years.
A much smaller proportion of patients may develop Crohn's
between the ages of 50 and 70 years but the disease can
occur in people of any age. The cause of Crohn's disease
is unknown, although a family history of IBD has been associated
with increased risk of an individual developing the disease.
About 20% of people with Crohn's disease have a blood relative
with some form of IBD, most often a sibling and sometimes
a parent or child. Cigarette smoking has also been shown
to contribute to the development or exacerbation of Crohn's
disease.
Causes
The inflammation in Crohn's disease has in
the past been thought to be related to abnormalities in
the body's immune system. The immune system is composed
of cells and proteins that normally protect the body from
infections and foreign bodies. In healthy individuals, there
is usually no immune response directed against food, 'good'
bacteria or other normal bowel components. In patients with
Crohn's disease however, the immune system seems to overreact
to substances and bacteria in the intestine. White blood
cells invade the intestinal lining and produce inflammatory
toxins causing chronic tissue swelling, injury and ulceration.
The precise cause of this abnormal immune response is unknown
although the existence of a specific infectious agent has
not been disproved. There also seems to be a genetic or
inherited predisposition to develop Crohn's disease. First-degree
relatives (brother, sister, parent or child) of patients
with Crohn's are more likely to develop the disease. Furthermore,
certain chromosomal markers have been found in the DNA of
patients with Crohn's disease. Crohn's disease is not caused
by stress.
For years, scientists have been searching
for an infectious cause of Crohn's disease. A growing body
of evidence suggests that a bacterium called Mycobacterium
avium subspecies paratuberculosis (MAP) may infect a genetically
susceptible subgroup of the population resulting in Crohn's
disease. Researchers here at the Centre for Digestive Diseases
have been instrumental in revealing this possibility and
remain at the frontline of international research into this
area.
Symptoms  
The most common symptoms associated with Crohn's
disease include abdominal pain, often in the right lower
quadrant, and diarrhoea. Rectal bleeding, loss of appetite,
fever and weight loss may also occur. Bleeding may persist
and cause anaemia. Because Crohn's is a chronic disease,
patients will experience periods of aggravation of symptoms
and other periods of remission. During periods of active
symptoms, patients may experience fatigue, joint pain and
skin problems. Some patients may experience symptoms ranging
from mild to severe. Children with Crohn's disease may suffer
delayed development and stunted growth.
People with Crohn's disease may feel well
and be free of symptoms for substantial spans of time when
their disease is not active. Despite the need to take medication
for long periods of time and occasional hospitalizations,
most people with Crohn's disease are able to hold jobs,
raise families, and function successfully at home and in
society.
Complications
Complications may develop as a consequence
of the chronic inflammation in Crohn's disease. These are
usually only manifest in severe disease. The most common
complication is blockage or obstruction of the intestine.
Stiffening and narrowing of the bowel wall causes obstruction,
which may result in constipation and poor absorption of
nutrients leading to malnutrition. Some patients may develop
tears in the lining of the anus (fissures). Inflammation
may, in some cases, cause a fistula to form. This is a tunnel
joining different loops of the bowel or connecting a portion
of bowel to the bladder, vagina or the skin near the anus.
Nutritional complications are common in Crohn's
disease, including deficiencies of certain proteins, calories
and vitamins. Other complications associated with Crohn's
disease include arthritis, skin problems, inflammation of
the eyes and mouth, kidney or gall stones and liver disease.
These problems often resolve with appropriate management
for the inflammatory process, but sometimes require separate
treatment.
Diagnosis
Crohn's disease can be difficult to diagnose
because its symptoms are similar to those of other GI disorders
such as ulcerative colitis irritable bowel syndrome. To
determine a diagnosis of Crohn's disease, the Gastroenterologist
must first obtain an accurate medical history from the patient,
then perform a thorough physical examination and a series
of other special investigations. Laboratory tests and x-rays
are useful, often to exclude other forms of intestinal inflammation.
Blood tests may be performed to check for anaemia, or high
white blood cell count, which may indicate inflammation.
Stools may be examined for occult bleeding or infection
with a specific pathogen. The small intestine may be viewed
with an upper GI x-ray after the patient swallows a chalky
solution containing barium. The barium reveals areas of
inflammation and other abnormalities in the bowel.
Colonoscopic procedures specifically aid diagnosis
by allowing the doctor to visualise the bowel directly using
a long flexible tube inserted into the anus equipped with
a miniature camera. The doctor is able to see inflammation,
ulceration and bleeding. A biopsy may also be taken, which
involves the removal of a sample of intestinal tissue, for
pathological testing to further confirm the extent and severity
of inflammation.
Treatment
Treatment for Crohn's disease depends on the
location and severity of disease, complications and response
to previous treatment. The goals of current treatment strategies
are to control inflammation, relieve symptoms and correct
nutritional deficiencies. At this time, treatment can help
control the disease, but there is no cure. Patients with
Crohn's disease may need medical care for a long time with
regular doctor visits to monitor the condition.
Nutritional supplementation
Nutritional supplements may be recommended,
especially in children with impeded growth and development.
Special high-calorie liquid formulas are sometimes used
for this purpose. A small number of patients with absorption
problems or malnutrition may require feeding by vein.
Anti-inflammatory agents
The class of drugs known as aminosalicylates
(5-ASA) are used to treat mild to moderate inflammation
in Crohn's disease. By controlling inflammation, these
drugs are generally effective at inducing and maintaining
remission of disease. They include sulphasalazine, mesalazine,
olsalazine and balsalazide. Possible side effects of 5-ASA
preparations include nausea, vomiting, heartburn, diarrhoea
and headache.
Immunosuppressive agents
Some patients take corticosteroids to control
inflammation. These drugs non-specifically suppress the
immune system and are used to treat moderate to severe
Crohn's disease. They treat the acute stages of disease
by dramatically reducing fever and diarrhoea, relieving
abdominal pain and tenderness, and improving appetite
and general sense of well-being. They include prednisone
in oral and rectal forms, i.v. hydrocortisone and budesonide,
oral or enema. Long-term corticosteroid therapy can induce
serious side effects, most notably skin and bone changes
and greater susceptibility to infection, and should be
avoided if possible.
Other immunosuppressive agents work by specifically
blocking the immune reaction that contributes to the inflammation
in Crohn's disease. Azathioprine and 6-mercaptopurine
improve overall clinical status, decrease the need for
corticosteroids and help to maintain remission. Their
action may not take effect for 3-6 months however and
their use must be closely monitored for side effects such
as nausea, vomiting, diarrhoea, allergy, decreased white
blood cell count and pancreatitis. Other immunomodifiers
such as methotrexate, cyclosporine and infliximab are
sometimes used to treat severe Crohn's disease that is
non-responsive to other forms of treatment.
Antibiotic agents
Accumulating data suggests that the bacterium,
Mycobacterium avium paratuberculosis (MAP), may be involved
in the development and persistence of inflammation in
Crohn's disease (www.crohns.org).
Antimycobacterial agents specifically targeting this potential
causative pathogen have shown success in inducing remission
and even possible cure of severe disease. The Centre for
Digestive Diseases is a leader in this area of research
and recently an Australia-wide trial has been completed
against MAP, the results of which will soon become available.
Certain clinical trials have also shown that broad-spectrum
antibiotics such as metronidazole, ampicillin and ciprofloxacin
drugs also have some short term benefit in the treatment
of Crohn's disease. The true value of these antimicrobial
drugs is yet to be determined.
Surgery
Patients with Crohn's disease may eventually
require surgery. The patient makes this decision after
close consideration of information given by doctors, nurses,
other patients and support groups.
Research
Crohn's disease research has traditionally
focussed on effective therapeutic relief of inflammatory
symptoms. Recent efforts have shifted towards identifying
specific infectious agents that may cause the disease.
By targeting the particular causative agent with certain
drugs, cure of Crohn's disease is theoretically possible.
-
Anti-MAP. The bacterium, Mycobacterium avium
paratuberculosis (MAP), is the best candidate for an
infectious cause of Crohn's disease. Small preliminary
trials using drugs that specifically target these bacteria
have shown promising results in Crohn's patients. Professor
John Hermon-Taylor, of St George's Hospital, London
first used double therapy consisting of the antibiotics,
rifabutin and clarithromycin, obtaining marked reductions
in inflammation, and in clinical symptoms in patients
with severe Crohn's disease. Improving on the dose and
composition of the therapy, a group of researchers led
by Dr Thomas Borody at the Centre for Digestive Diseases
achieved remarkable and dramatic reversal of inflammation
in patients with Crohn's disease, resulting in long-term
regression of symptoms and inflammation in most patients.
A major Australian multi-centre clinical trial of antibiotic
therapy directed at MAP is now under way to formally
test this radical new treatment for the disease.
Researchers continue to look for more effective treatments.
Other examples of investigational treatments include:
-
Anti-TNF. Research has shown that cells
affected by Crohn's disease contain an inflammatory
protein produced by the immune system called tumour
necrosis factor (TNF). This cytokine may be responsible
for the inflammation in Crohn's disease. Anti-TNF
(eg. infliximab) finds TNF in the bloodstream, binds
to it and removes it before it can cause inflammation
in the intestine. In studies anti-TNF seems particularly
helpful in closing fistulas. The restricted drug,
thalidomide, also has anti-TNF properties and is
being carefully investigated as a possible treatment
for severe Crohn's disease.
-
Interleukin-10. Researchers are studying
the effectiveness of synthetic IL-10 in treating
Crohn's disease because this cytokine may help to
suppress inflammation.
-
Budesonide. This new corticosteroid has
recently been identified. Studies are revealing
that this drug may have fewer side effects than
other corticosteroids.
-
Methotrexate and Cyclosporine. These are
immunosuppressive medications that may be useful
in severe Crohn's disease and appear to work faster
than traditional immunosuppressants.
-
Zinc. Free radicals are molecules produced
during fat metabolism, stress and infection among
other things that may play a role in inflammation
by causing cell damage. Zinc removes free radicals
from the bloodstream. It is possible that zinc supplementation
might help reduce the inflammation in Crohn's disease.
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