Crohn's Disease: Causes and Risk Factors
1. Introduction
To define Crohn's Disease (CD), one can say that it is a chronic, inflammatory condition of the gastrointestinal tract, which can affect anywhere between the mouth and the anus (skip to 1.4). The symptoms of CD may vary from mild to severe and can change over time. The main symptoms are abdominal pain and diarrhea, due to inflammation of the small bowel or colitis. Patients may also have rectal bleeding, weight loss, fevers, and suffer from a lack of energy. There are also a number of extra-intestinal problems that can occur during the course of the disease such as arthritis and skin rashes. The disease typically follows a relapsing and remitting course and there may be periods of time where there are no symptoms at all (CDAI). A small proportion of patients may develop serious disease requiring surgery, usually to treat complications of the disease, which is defined as penetrating or stricturing CD.
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1.1 Definition of Crohn's Disease
Although Crohn's disease is currently not curable, it is treated with various treatment methods in hopes of achieving remission. Treatment of Crohn's disease includes anti-inflammatory drugs to control mild to moderate disease, antibiotics, corticosteroids for short-term usage to rapidly control active disease, drugs to suppress the immune system, and biologic therapy. While there is no known medical cure for moderate to severe Crohn's disease, one in every eight persons finds relief and resolution by having the ileal portion of the small intestine removed, also known as an ileoectomy. The ileum is the most commonly affected area of the small intestine and may present with symptoms of pain in the right lower abdomen and weight loss. Because the disease is characterized by abnormal immune system activation, there is currently research being done on the use of immunosuppressive agents for longer-term usage in maintaining remission of the disease. Further research into the pathophysiology of the disease may lead to early diagnosis of Crohn's disease before it causes symptoms, and thus disease prevention. In addition, it is now recognized that genetic predisposition, environmental factors, and an abnormal immune system response are all factors involved in the pathogenesis of the disease. While there is no known causative environmental factor, maintaining a healthy lifestyle and consuming a balanced diet has been favored by individuals with the disease in maintaining good health and possibly preventing a recurrence of symptoms. A cure for the disease is part of current medical research.
Crohn's disease is an inflammatory bowel disease (IBD). It causes inflammation of the lining of your digestive tract, which can lead to abdominal pain, severe diarrhea, and even malnutrition. Inflammation caused by Crohn's disease can involve different areas of the digestive tract in different people. The inflammation caused by Crohn's disease often spreads deep into the layers of affected bowel tissue. Crohn's disease can be both painful and debilitating, and sometimes may lead to life-threatening complications. Although it may involve any part of the digestive tract from the mouth to the anus, it most commonly affects the small intestine and/or the colon. Among IBD patients, the disease has historically been known to cause greater surgical requirements in the elderly. With the use of certain medications, and sometimes surgery, it has been possible to achieve periods of symptom-free remission, and the number of individuals with the disease in the U.S. on a yearly basis is not well documented. Once it has been diagnosed, the disease is generally a lifelong recurrence of periods of flare-ups and remission.
2. Causes of Crohn's Disease
Environmental factors are also thought to play a role in the development of Crohn's disease. Smokers are two times more likely than non-smokers to develop Crohn's disease. Recent evidence has shown that smoking may accelerate the progression of Crohn's disease and quitting smoking may reduce the activity of the disease. Nonsteroidal anti-inflammatory drugs, such as aspirin and ibuprofen, have also been associated with an increased risk of Crohn's disease. Certain antibiotics have also been shown to increase the risk of Crohn's disease. A study in 2006 concluded that appendectomy may reduce the risk of Crohn's disease but increase the risk of developing ulcerative colitis.
Genetic factors are believed to play a role in approximately one third of the population diagnosed with Crohn's disease. People of Ashkenazi Jewish descent are four to five times more likely to develop Crohn's disease than the general population. Some studies have also shown that genetic mutations that lead to a faulty immune response have been associated with Crohn's disease. In 2001, research identified a gene on chromosome 16 thought to be associated with Crohn's disease. Further research into this gene could lead to an understanding of how Crohn's disease develops. In 2006, research showed that a rare genetic mutation causing an autosomal recessive disorder in the IL10 signaling pathway resulted in a very early onset form of Crohn's disease. This suggests that certain genetic mutations can lead to a faulty immune system and ultimately result in the development of Crohn's disease. Other studies have shown that first-degree relatives of a person with Crohn's disease are 8 times more likely to develop the disease than the general population.
2.1 Genetic Factors
Recent studies indicate that the immediate cause of CD is an imbalanced immune response resulting from interaction between genes and the environment. Although the picture is not completely clear yet, both genetic and environmental factors are believed to be involved. There is strong evidence in some families with more than one affected relative, indicating that a person's genetic make-up may make them more susceptible to CD. Recent technological advances have improved our ability to investigate genetic material of living organisms. Using these techniques, scientists have been able to target specific genes for investigation, and believe they are getting closer to identifying genes which may increase susceptibility to CD. CD is a complex and multifaceted illness, and it is likely that many genes, each with a relatively small effect, contribute to a person's susceptibility to CD. This can make investigations difficult, because it is likely that a gene identified as having an association with CD may have no impact upon an individual's susceptibility to the disease, and may also impact other, unrelated characteristics of the individual's biology. Identification of a gene associated to a susceptibility to CD presents future potential for predicting risk of developing the disease and possibly blocking the disease before any symptoms have arisen.
2.2 Environmental Factors
There are many environmental factors that may contribute to the development of Crohn's disease. The gastrointestinal disease for which Crohn's disease is an inflammatory form that affects any part of the digestive tract. The disease is thought to be due to an interaction of genetic and environmental factors. These environmental factors have been largely speculative and a comprehensive review proposes the following as a list of some of the more likely environmental triggers. Infectious agents can cause Crohn's in various ways and several organisms have been implicated. Mycobacterium avium subspecies paratuberculosis (MAP) has been suggested as the cause of Crohn's in some patients due to its ability to cause a similar disease in animals. Studies on this organism are ongoing and a definitive answer has yet to be reached. Other mycobacteria are also prime suspects. They have been shown to activate NOD2 and cause a Crohn's like disease in mice. Amebiasis is a disease caused by the protozoan Entamoeba histolytica and E. histolytica has been detected and isolated more frequently from the stool of Crohn's patients compared to healthy individuals. Whether this higher detection rate actually indicates a cause of Crohn's is uncertain. Another example is Yersinia. Yersinia can cause an ileitis similar to Crohn's disease and it has also been isolated more frequently in Crohn's patients. Viruses can also cause Crohn's disease and the often theorized role of a virus in a chronic inflammatory disease is the cause of an abnormal immune response due to molecular mimicry. This happens when an infection induces an immune response that results in damage to self-tissue. Often this immune response can be switched on and off. An epidemiological approach to studying this is to compare the prevalence of Crohn's disease to the prevalence of a certain infection in different countries.
2.3 Immune System Dysfunction
Immune system dysfunction is a key factor in the pathological reactions that occur in Crohn's disease. The immune system is important in recognizing foreign material and microorganisms and mounting an immune response against them. In Crohn's disease, it is believed that the immune system responds inappropriately to normal constituents of the GI tract. This, in turn, leads to the recruitment of white blood cells into the lining of the intestines. The activated immune system produces inflammation. There is a vast amount of evidence supporting the role of the immune system in causing the inflammation in Crohn's disease. Firstly, drugs that selectively block immune responses help to reduce inflammation and bring about a remission in symptoms. An example of such a drug is infliximab, which is a monoclonal antibody that targets TNFα, a protein involved in causing inflammation. Secondly, removal of white blood cells from the blood and re-injection of these cells after some weeks leads to the migration of these cells into the intestines and flaring of Crohn's disease.
3. Risk Factors for Crohn's Disease
Those factors that lead to an increased risk of developing Crohn's disease are still not fully understood due to the complexity of the disease. However, there are several factors which have shown to increase the risk of developing Crohn's. These include family history, smoking, age and gender, ethnicity, and geographical location. Family history of Crohn's is one of the biggest risk factors in developing the disease. Those with first-degree relatives with Crohn's have been found to have a relative risk of developing the disease ten times higher than the general population. Family history shows there must be a genetic predisposition to developing the disease; however, the specific genes involved have not yet been fully discovered. Twin studies have further shown that identical twins have a 55% chance of developing the disease if their twin has it compared with a 5% chance in non-identical twins. Smokers have also been found to have a significantly higher risk of developing Crohn's disease compared to non-smokers. There is an association between the severity of the disease and the amount smoked, as well as smoking has been found to reduce response to treatment. It is unclear why smoking increases the risk; however, it is widely agreed that smoking and its association with Crohn's is a public health concern. The disease has been found to be more common in those who are under 30, have white European descent, and live in urban areas compared to those who are older, of other races, and live in rural areas. This must mean that age, gender, ethnicity, and geography are all risk factors in the development of Crohn's disease; however, the explanations for these findings are still unknown.
3.1 Family History
Family history is the strongest risk factor for Crohn's disease. About 20% of people with Crohn's disease have a blood relative with some form of inflammatory bowel disease, most often a brother or sister and sometimes a parent or child. The risk is highest if the affected relative has Crohn's disease or if the relative was diagnosed at a younger age. This does not mean that children will inevitably develop Crohn's disease if a parent has it. Researchers have identified several genes that may be linked to IBD. The best studied of these genes, called NOD2, was reported in 2001 to be associated with Crohn's disease. This discovery has improved our understanding of the causes of IBD and is leading to insights about the genetic factors involved in Crohn's disease. Although genetic factors are important, most researchers believe that Crohn's disease is caused by an abnormal immune response to bacteria in the digestive tract. Studies are under way to test this theory. One study supported by the NIH found that a protein produced by white blood cells, called interleukin-21, plays a key role in directing the abnormal immune response in animals with IBD. This finding could ultimately lead to new treatments to restore the normal balance of the immune system in people with IBD and other autoimmune diseases.
3.2 Smoking
One of the main environmental factors that has been repeatedly associated with Crohn's disease is smoking. This association may appear unremarkable given the commonality of smoking, however the strength of the association is incredibly high. Smokers have been quoted as having a two to four fold increase in development of the disease compared to non-smokers. Furthermore, it has been well documented that smoking has an adverse effect on the clinical course of the disease. Indeed, giving up smoking has been shown to reduce the amount of drug therapy, surgery, and hospital admissions required by those diagnosed with Crohn's disease. In particular, the risk of ileal disease and the requirement for surgical resection among smokers has been shown to be significantly higher than that of non-smokers. The mechanism behind why smoking is a risk factor for developing Crohn's disease has not been fully elaborated. It is known that smoking has very diverse effects on the immune system and some of these effects could be specific to the development of an abnormal immune response in Crohn's disease. An epidemiologic study found suggestion that exposure to smoke in utero or as a child may also increase the risk of developing Crohn's disease, indicating that this could be a period of vulnerability for the effects of smoke on the immune system to bring about IBD in later life.
3.3 Age and Gender
Crohn's disease affects both males and females, with the highest peak of diagnoses occurring between the ages of 15 and 35. Children under the age of 18 account for approximately 20% of all cases, with the first peak age-specific incidence occurring between the ages of 16-19. It is clear that Crohn's tends to affect young people more often than the elderly. There have been a number of new cases diagnosed in people over the age of 75, however, it is very rare. This means that elderly people are unlikely to have complications from Crohn's disease, as it is generally a disease where you suffer with symptoms for much of your life. Older people are more likely to be diagnosed with a different form of IBD called Microscopic Colitis. Females are slightly more likely than males to be diagnosed with Crohn's disease, unlike Ulcerative Colitis which has a relatively equal gender incidence. Estrogen and its metabolites have been theorized to increase the risk of developing Crohn's disease in females, however, medical evidence for this is inconclusive. Another theory is that women are more likely to seek medical care and be honest about their symptoms with a doctor, leading them to be more often diagnosed than men with similar symptoms.
3.4 Ethnicity
Summary Points: - There are distinct differences between ulcerative colitis and Crohn's disease in the distribution of ages at diagnosis and in the sex of patients affected. - There is evidence that both diseases are becoming increasingly common in the developing world, whether measured by incidence in migrants from low-incidence areas to high-incidence areas, or increasing incidence over time. - Increasing globalization may influence the incidence of Crohn's disease and/or alter its disease course; features of a western lifestyle have been associated with subsequent development of inflammatory bowel disease.
Evidence also indicates that Crohn's disease is more common among adolescents and young adults, with the highest incidence around ages 15-25. Crohn's disease is more prevalent among females and has been associated with oral contraceptive use. The reasons for and the implications of these demographic discrepancies are not well understood. High levels of disease in young people and throughout reproductive years may have implications for the optimal use of therapies.
3.5 Geographic Location
Infection with various microorganisms is implicated in Crohn's disease, and it is possible that it may be caused by a chronic infection with a new or unusual organism. Stress is associated with the onset and exacerbation of inflammatory bowel disease, but its role in the development of Crohn's disease is not certain.
Various environmental factors have been postulated, including infections, diet, smoking, oral contraceptive use, and stress. The association with cigarette smoking is well known, as smokers are twice as likely to develop Crohn's disease than non-smokers and have more severe disease. The impact of diet on the development of Crohn's disease is still unclear, and the role of specific dietary components has yet to be identified.
Twin studies and familial aggregation data indicate that patients with a family history of inflammatory bowel disease are more likely to develop Crohn's disease. This indicates that shared environmental factors and gene-environment interactions may contribute to the development of Crohn's disease in these families. These environmental factors may be linked to the migration of susceptible populations to different geographic areas.
Multiple studies have shown that the prevalence of Crohn's disease varies widely between different geographic areas, with the higher incidence in northern climates and urban areas. In the United States, it is more common in the northern states than in the south, and it is more common in Canada than in the United States. Its incidence is increasing in developing nations, possibly due to a more westernized lifestyle.