Polygenic score
Influential genes: NOD2,IL10,NLRP12
NOD2 is a gene that plays a role in the innate immune system. Mutations in the NOD2 gene have been strongly associated with an increased risk of developing Crohn's disease.
IL10 helps maintain the balance between pro-inflammatory and anti-inflammatory responses in the gut. Genetic variations in IL10 have been linked to an increased risk of developing Crohn's disease.
NLRP12 gene variations are linked to an elevated risk of Crohn's disease. NLRP12 regulates inflammatory cytokine production and influences the immune response in the gut.
Crohn's disease (CD) is a chronic inflammatory condition that can affect any part of the gastrointestinal tract. No singular cause of the disease has been identified, and the mechanism by which it arises is incompletely understood. It is an autoimmune disorder, in which the body’s own immune system attacks the body’s digestive tract. It is generally accepted that a plethora of contributing factors is at play in CD, including immunological, environmental, and genetic. CD manifests with so-called ‘skip lesions’, i.e. patches of transmural inflammation of any part of the gastrointestinal tract, with stretches of normal tissue in between. The inflammation can lead to a number of debilitating symptoms, such as chronic abdominal pain, perianal fistulas, diarrhea, and constipation.
The prevalence of CD differs based on the region, with the highest being in Europe (322 cases per 100,000 people in Germany) and Canada (319 cases per 100,000)2. Although the pathogenesis of CD is very complex, the increase in the number of new cases in the recently industrialized countries hints at environmental risk factors common in Western and industrialized societies – including mainly diet and lifestyle. Studies on people who have emigrated from a non-industrialized country to an industrialized destination have shown an increased risk of developing CD, compared with the general population.
The only modifiable risk factor for Crohn’s disease that has been identified is smoking. It increases the risk of CD by a factor of 2, while, however, being dependent on gender, age, and ethnicity. Furthermore, one of the commonly described features of CD is a change in the composition of the intestinal microbiome, which has a proven effect on the immunological functioning of the gut. Among many other influencing factors, diet is extremely likely to have an effect on the microbiome, which has the capability of dynamic change. Low fiber intake and frequent switching between high-fiber and low-fiber food have led to unfavorable changes in the gut microbiome, leading to an increased risk of developing CD. On the other hand, adhering to a Mediterranean diet has proven itself beneficial in terms of the development of late-onset Crohn's disease.
The genetic component of Crohn's disease has been researched heavily in recent years. Concordance rates of CD among monozygotic twins (as determined by twin studies) have been estimated at ~50%, which is higher than in ulcerative colitis, the other major inflammatory bowel disease. A well-known coding variation in the gene NOD2 is known to be selectively associated with CD risk. Nevertheless, there are more than 200 various genetic loci that have been associated with CD. Each of these, however, increases the risk only by a relatively small percentage. It has been shown that only ~13-13.5% of the heritability of CD can be explained by strictly genetic factors6, which hints at the relatively high importance of epigenetic and environmental factors (such as cultural diet).
The most common problems of patients with Crohn's disease include recurrent abdominal pain, chronic diarrhea, and unintentional weight loss. These digestive complications arise due to ulcers which are a result of the ongoing inflammation in the digestive wall. The most commonly affected part of the tract is the ileum – the last part of the small intestine. There are also less common symptoms pertaining to the body outside of the digestive tract, such as joint and skin problems, and eye redness.
There are multiple types of Crohn's disease, based on the clinical picture they give rise to: inflammatory, fibrostenotic (scar tissue causes narrowing of the section of the gastrointestinal tract), and penetrating (fistulas between various parts of the tract arise). These types can all occur in the same patient. CD symptoms typically occur in variable cycles of flares and periods of remission. Ongoing treatment during both flares and remission is vital to increase the chance of long periods without symptoms.
Diagnosis of CD is not based on a singular clinical finding and thus it can be challenging for the clinician. The gold standard method for establishing a diagnosis of Crohn's disease is ileocolonoscopy, and by taking a biopsy. However, in order to make a definite diagnosis, a holistic approach must be employed, involving assessment of symptoms, imaging, as well as biomarkers. Most commonly used biomarkers are ASCA (positive rate in CD is around 60-70%)5, and fecal calprotectin. Calprotectin is a protein which is present in neutrophils (i.e. immune cells), and is released in inflammation. Its presence in feces is both sensitive and specific for CD. There are also other modalities, such as small-bowel capsule endoscopy, in which a small capsule is swallowed and it wirelessly transmits images of the intestinal lining to a computer – however, this is reserved for specifically indicated patients. For the purpose of fully assessing the disease, ultrasound, CT and MRI are crucial.
The management of Crohn’s disease has developed significantly over the past 10 years, and it includes both pharmacological and surgical approaches. The primary objectives of care are steroid-free remission, increased quality of life, and low number of complications.
The main focus of pharmacological therapy is to achieve healing of the intestinal mucosa. This is associated with improved outcomes for the patients both in the short-term and the long run. How this is achieved is based on stratification of the patients, according to their age, part of intestine affected, severity, and other prognostic factors. Most commonly used medications include steroids, 5-aminosalicylates and sulfasalazine, immunomodulators, and biologic response modifiers. All of these aim at reducing the inflammation in the wall of the intestine. There are specific indications and contraindications for each of these that should be consulted with the treating physician.
The surgical approach is used when medication no longer suffices in controlling the symptoms and problems associated with CD. Most CD patients will need surgery at some point throughout the disease progression. Among the most common surgeries for CD is the removal of the diseased parts of the intestine/colon, and strictureplasty, i.e. opening sections of critically narrowed bowel that lead to blockages.
There is no definitive method to prevent Crohn’s disease. However, smoking cessation has great benefits also in this area. Moreover, consuming a diverse, full mediterranean-style diet can be of benefit.
Crohn’s disease is a chronic, progressive and destructive disease. There are multiple prognostic factors, such as age at diagnosis, smoking, disease duration, laboratory marker levels, deep ulcers on endoscopy etc., which are associated with a worse prognosis. This translates to a possibly higher risk of relapse and/or a more complicated disease progression. Moreover, extensive CD also predisposes to colon cancer and thus all CD patients are recommended to start screening colonoscopy early.
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