• Inflammatory Bowel
• Genetics of IBD
• Cancer risk in IBD

Normal colon - no inflammation

What is inflammatory bowel disease (IBD)?

This is a collective term for the two main conditions:

• Ulcerative colitis and Crohn’s disease are inflammatory diseases of the gastrointestinal tract.
  • This is different from irritable bowel (IBS) where no inflammation is present.
  • These conditions have no known cause.
    • They are not caused by an infection.
    • They are not caused by any particular type of diet.
    • They are not caused by stress.
  • The diagnosis is made by the combination of tests - not by one particular test.
  • Ulcerative colitis and Crohn’s disease have many features in common BUT are probably best considered as separate diseases.
    • There has been an increasing incidence of Crohn’s disease in recent years.
    • The incidence of ulcerative colitis has remained about the same in western countries.
      
• In NZ 1:700 people have Crohn’s disease.
  • It is more common western countries (Northern Europe, North America and Australia and New Zealand).
  • Now becoming more common throughout the world.
    
• Smoking.
  • Increases the risk of Crohn’s disease.
  • Decreases the risk of getting ulcerative colitis.
    
• There is clearly a major influence of genetics.
  • First-degree relatives have a 30-fold increased risk of developing Crohn’s disease.
    • This means an 8% lifetime risk for first-degree relatives.
  • There is a genetic influence in ulcerative colitis but this is less prominent.

The role of genetics in inflammatory bowel disease

• There are three main lines of evidence.
  • IBD is more or less common in some ethnic groups.For example, in New Zealand, IBD is very uncommon in Maori or Pacific Islanders.
  • There is clustering of disease within families. About 25% of individuals with IBD know of another family member with IBD. The lifetime risk for a first-degree relative (siblings or parent-child) developing IBD is 10%.
    
  • The most compelling evidence comes from identical twin studies.
    • These studies show there is a 1/3rd chance of a twin developing Croh'ns disease is if the first affected twin has Crohn’s disease.
    • For ulcerative colitis the chance of the second twin having colitis is 7%.
    • This is called concordance (both twins having inflammatory bowel disease).
    • Mostly the type of IBD is the same – i.e both ulcerative colitis or both Crohn’s disease.
    • But sometimes one twin has UC and the other Crohn’s disease.
  • This pattern is observed in some families were both types of IBD occur. This suggests that there is some genetic overlap.
    • For example, it may be that genes A, B, C and D = susceptibility to Crohn’s disease and genes C, D, E and F = susceptibility to ulcerative colitis.
  • It has been observed that IBD is more likely to occur at an early age if there is a strong family history of IBD.
    • This could be termed  “genetic loading” - inheriting 5-7 important genes rather than 3-5 genes may impact on the nature of the condition.
  • The magnitude of the genetic effect can be seen when comparing non-identical and identical twins. Only 4% of non-identical twins develop IBD (where the first affected twin had Crohn’s disease) compared with a 1/3 risk for identical twins 
    • The genetic susceptibility in IBD is clearly not a simple inheritance pattern as is seem in disease that are caused by a single gene.

• There must be several genes involved (perhaps 5-10 genes) – some more important than others.
  • This sort of multi-gene susceptibility pattern is akin to the situation that is likely to occur other conditions like hypertension and diabetes.
  • IBD is one of the “multi-gene” conditions with the strongest “genetic susceptibility”.
  • The genetic risk appears to be most obvious in Crohn’s disease (compared with ulcerative colitis).
  • It also seems that genetic background explains more than just the diagnosis.
    • In families with Crohn’s disease it is common to have a similar type of disease.
    • i.e the same of bowel is involved.
  
  
• While the knowledge of the genetic risk has been known for a long time the technology has not been available to search for these genes
  • It has been very much a "needle in the haystack" problem without any clues were to start.
  • The problem has been solved using genome-wide scans using automated techniques that pick-up “hot spots” of interest.
  • This has required collecting blood samples from sibling pairs (brother/sister etc combinations).
  • Several large DNA banks have been created in Europe and USA and also in Australia.
  • The nutragenomics study group in Auckland has also been involved in these studies.
  • The Human Genome project is a big help because a researcher can “look up” the genes that are within an area of interest to try and “pre-guess” genes that might have something to do with causing the disease.
  • Possible genes are not always obvious contenders because of our lack of understanding of the cause of IBD.

• The NOD 2 gene.
  • This gene has something to do with the way the immune system responses to “normal” bacteria in the bowel. This initial insight is exciting.
  • People who have NOD2 mutations tend to have disease in the ileum (small bowel) and are more likely to require an operation to remove this section of bowel.
    
• Research into Crohn’s disease suggests that it is;
  • not the result of a particular infection or bacteria.
  • but is the result of an abnormal response of the body’s immune system to normal bacteria.
  • It seems that with a particular set of genes the immune system is unable to adequately “switch off” the inflammatory response.
• The exact way changes in this gene and other genes yet to be discovered affect response to bacteria will be crucial information and will hopefully led to significant advances in our knowledge of the cause of the disease.  This is the field of interest for a study at the Department of Molecular Medicine, School of Medicine, University of Auckland.

• Firstly, an improved understanding of the disease will lead to new types of treatment.
  • We have already seen how research into mechanisms of inflammation can lead to treatment.
  • The central role of a molecule called TNF (tumour necrosis factor) lead to the development of a blocking antibody (infliximab (Remecaide)and adalimumab (Humira) – the first genuine new treatment for Crohn’s disease for many years.
    
• Secondly, it may lead to new diagnostic tests.
  • Often the distinction between Crohn’s disease and ulcerative colitis is difficult and sometimes making the correct diagnosis is very important.
  • It may be that genetic tests will further define different groups.
    
• Genetic testing could be led to a better choice of treatments.
  • Knowing who will response better to different treatments.
  • Perhaps also knowing who will have more aggressive disease and require more intensive treatment at an earlier stage.

What is the risk of developing colon cancer in ulcerative colitis?

• It has been active for at least 10 years and,
• the disease involves at least half of the colon.
• The degree of risk is difficult to estimate.
  • The main underlying cause is "chronic" inflammation.
  • If the disease has settled then the risk is significantly lower.
  • A family history of colon cancer increases the risk.
• From point of view of most practising gastroenterologists today it seems exceptionally rare to have a death from colon cancer that has arisen in a patient with ulcerative colitis.
• There are widely differing reported risks from different countries.
  • In fact, two studies, one from Denmark and one from Israel have suggested that the rate of colorectal cancer for their clinic population was no different from the general population.
  • Unfortunately no data are available from New Zealand.
• The degree of risk of colorectal cancer in ulcerative colitis may be decreasing over recent decades.
  • The reasons for this observation are unclear.
  • There is good evidence that maintenance treatment with 5-ASA compounds(that is Salazopyrin, Pentasa, Asacol, Dipentum) decreases the risk of colorectal cancer.
  • Increasing use of these medications may be an explanation.
• Regular clinic follow-up is also associated with decreased risk.

Screening colonoscopies.

• Many studies have shown that regular colonoscopies are effective in detecting early colon cancers.
  • The main aim is to identify changes that predict an increased risk of colorectal cancer.
  • That is pre-cancer changes or dysplasia.
• It is difficult to run a comprehensive screening program.
  • All studies have shown that more cancers are diagnosed outside of the screening programme.
  • Less than half of patients stay in a regular surveillance programme (for whatever reasons).
• The frequency of screening procedures required to reduce the risk of colorectal cancer is debated.
  • Shorter intervals between procedures may be better but public funding of health requires strong evidence for cost-effectiveness.
  • A reasonable compromise is 3-yearly colonoscopy after 10 years of ulcerative colitis.
  • The well motivated person with ulcerative colitis should have surveillance colonoscopy at an interval of 2 yearly after 8 years of the diagnosis.
• When is an operation (colectomy) required?
  • See ulcerative colitis section for details on surgery.
  • If there is any dysplasia (changes on microscopic examination of biopsies) then a repeat colonoscopy in 6 months is required.
  • If the changes are severe, then an operation is required to prevent the formation of cancer of the colon.
  • When the colon is removed there is no longer any risk.
  • Usually the risk of cancer is only a small part of decision to proceed to surgery.
    • The main issues are the current quality of life.
    • what improvement could be expected after surgery.
• There may be an increased risk of colon cancer with colonic Crohn's disease.
  • This risk is small (many studies have not shown any difference from the risk for the general population).
  • Regular surveillance by colonoscopy has not been the policy for most gastroenterology departments but should be considered on an individual basis.

• Regular clinic attendance and discussion of individual risks with your physician is sensible.
  
• The use of maintenance long-term 5-ASA drugs does appear to have some protective effects (50% decrease in risk).