What is Crohn’s disease?
Crohn’s disease (CD) is a clinical subtype of inflammatory bowel disease (IBD), involving the entire gastrointestinal tract typically the ileum or the colon. The ileum is the lower part of the small intestine and the colon is the large intestine. Chronic inflammatory disease can affect any part of the digestive system in varying periods of activity and remissions. Crohn’s disease is usually diagnosed after a person has sudden or acute pain in the abdomen or has severe pain lasting more than three to four weeks.
This auto-immune disorder is chronic and relapsing, with no agreed upon cause or cure. Individuals may have a genetic susceptibility which provokes an aberrant immune response whereby the body attacks itself. An imbalanced inflammatory immune response involves interplay between genetic, environmental, microbial, and immune factors. The inflammation is focal, asymmetric, or transmural.
The incidence of Crohn’s is increasing worldwide and posing a major public health threat. This disease affects an estimated 500,000 people in the United States. Researchers consider it a disease of the developed world, with typical patients being young and of urban origin. Western countries have seen dramatic increases in the last 100 years. Changes in lifestyle and dietary considerations seem to play a large role in increasing incidence. Processed, simple carbohydrates, have replaced natural, whole foods and increased inflammatory bowel diseases.
Patients have strictures or obstructions, and ileus or reduced bowel mobility which limits the action of the bowels, causing inflammation and pain. Diarrhea and bleeding are common when a partial or complete blockage of the intestines occurs. Perforations of the inflamed intestines cause a leakage of intestinal contents into the abdominal cavity. Formation of fistulas or an abnormal connection between two organs can result, which may trigger infection.
Inflammation of the liver, joints and eyes, skin rash and iron deficiencies can develop. Scarring in the intestine can cause problems with digestion of food and induce weight loss and nutritional deficiencies. Sometimes due to surgeries the intestines becomes too short and limit digestive processes. Treatment mostly consists of symptom relief, although researchers urge more aggressive treatment that goes beyond symptom relief. Life-long management is necessary as outbreaks and complications are unpredictable and variable.
Consequences and Complications
- Cancer – Crohn’s disease is one of the three highest risk factors for the development of colorectal cancer.
- Fitness – children and youth have 25% lower aerobic fitness levels and 10% lower muscle function. Poor fitness in childhood is a predictor for adult health.
- Pregnancy – can induce pre-term labor, low birth weight, and small for gestational age infants.
- Ears – a rare complication of hearing loss may result.
- Infections – since Crohn’s patients already have inflammation in the gut, and other areas, they are especially vulnerable to infection especially when admitted to the hospital.
- Post Traumatic Stress Disorder (PTSD) – develops due to severe pain, exhaustion and unpredictability. One in five patients may develop PTSD.
- Osteoporosis – osteoporosis, osteopenia and an overall higher rate of abnormal bone density can result from Vitamin D deficiency. Inadequate intake of all nutrients, malabsorbtion of Vitamin D, steroid use and genetic factors may be responsible for bone density deficits.
- Heart Disease – inflammation alters lipid metabolism and plaque development.
- Anxiety – bacteria in the gut may influence behavior and a high rate of mental illness is found in Crohn’s. Patients experience significant emotional distress that impairs their overall quality of life.
Causes of Crohn’s Disease
Scientists now believe that some genetic diseases have evolutionary value. This notion is counter-intuitive in that evolution should be reducing diseases but instead we are developing more. They believe what is happening is a trade-off to protect against even more disease-associated mutations. In other words, a person’s genome is a buffer which limits some conditions but raises the possibility of others. When civilizations move, change diet and climate, and come in contact with others the genome changes over time and contributes to disease conditions.
The Hygiene Hypothesis states that since bacteria is the link between the environment and the gut, interaction with bacteria systems or the lack thereof, contributes to Crohn’s disease. Scientists believe that increased hygiene and sanitation in developed countries contributes to asthma, allergies and autoimmune disorders like Crohn’s. People are not exposed to both harmful and helpful bacteria as much. One researcher believes women are particularly susceptible because they are socialized to stay inside and stay clean, whereas boys are encouraged to play outside in the dirt.
In support, occupations have been studied and blue collar workers (manual laborers in farming and manufacturing occupations) have lower incidence of Crohn’s than white collar workers (professionals like secretaries, teacher, sales workers, and managerial occupations). While not encouraging people to eat dirt, getting outside may force the immune system to adapt in positive ways.
The bacteria living in and on our bodies keep our systems running smoothly. Microbes in the colon outnumber the others and their effects on energy and the immune system are still being investigated. Certain bacteria may initiate Crohn’s disease in those who are genetically susceptible. When the microbes alter the immune system balance, inflammatory conditions result. Scientists would like to collect samples from people around the world who consume different diets to store, analyze, and perhaps introduce friendly microbes into the gastrointestinal tracts of patient’s with imbalanced bacteria colonies.
Genome-wide association studies (GWAS) help sort through DNA of individuals in order to identify genetic diseases and find treatments. Ninety-nine genome regions are associated with inflammatory bowel disease. Twenty-five per cent of Crohn’s disease patients have a mutation in NOD2 gene which may prevents bacteria from being properly recognized by the immune system. Mutations in gene expressing LRRK2 have been linked to an increased risk of Crohn’s disease. Ankylosing Spondylitis (AS) genes may share common mutations with Crohn’s. Celiac disease shares at least four genetic risks with Crohn’s disease, both inflammatory diseases of the gastrointestinal tract. Developing data on Crohn’s disease is important, as is an understanding of shared risks with other genes.
Vitamin D – reduced absorption of Vitamin D is found in patients with Crohn’s. Vitamin D is ingested through nutritional intake and is released in the skin from exposure to sunlight. Scientists found 2,776 binding sites for the Vitamin D receptor in the genome. A high concentration of binding sites is found near the genes associated with autoimmune conditions.
- A-20 proteins – defects in the A-20 protein can play a part in Crohn’s. A-20 can prevent apoptosis or cell death.
- Prostaglandin – levels of prostaglandin D2 were elevated in patients in long-term remission from Crohn’s, suggesting an important way to improve remission rates.
- IL-22 and IL-23 – these molecules are helpers in the early phase immune response. Their presence or absence modulates the downstream immune response.
- Th-17 – plays a harmful role in autoimmune diseases. Elevated levels may play a key role in early development of Crohn’s.
- IL-1R – essential for anti-inflammatory processes, but genetics, infection and some drugs inhibit its action.
- Hydroxylases – regulate water and salt transport in the intestines and may influence diarrhea sometimes caused by Crohn’s.
- Regulatory T cells (T-regs) – responsible for limiting the immune response. Since the autoimmune system in Crohn’s goes into overdrive, regulating the T-regs may have wide implications. These T-cells are known as suppressor cells. Replicating them in the laboratory and transplanting them into a patient has promise.
Crohn’s Disease Diagnosis
The strongest predictors of disease:
- Age – the age at the onset, between the ages of 20 and 30, is associated with more aggressive disease. Those diagnosed early in life are likely to have family members with inflammatory bowel disease. Developing Crohn’s later in life has better outcomes because as people age their immune systems tend to quiet down.
- Location – different types of locations including the upper gastrointestinal tract, small bowel and anal lesions are associated with risk of recurrence and surgery.
- Smoking Habit – smoking cigarettes increases disease onset and severity.
- Viral Infections – 30-50% of patients had Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections.
- Steroid treatment – 80% of patients had used steroids in the past.
- Family History – individuals with a family member with inflammatory bowel disease are more susceptible to Crohn’s disease.
Crohn’s Disease Symptoms
Abdominal pain often leads a person to seek treatment. Clinicians evaluate the symptoms and signs which leads to a series of sometimes invasive, costly and potentially dangerous investigations. Patients with more intense pain will visit a physician sooner, often in a hospital emergency room visit. The diagnosis depends on the nature of the pain, the intensity, the location of the pain and sensitivity to palpation. Usually these symptoms are enough to indicate the location of the sick organ. But, sometimes Crohn’s pain symptoms in the right lower quadrant of the abdomen mimics acute appendicitis. Other symptoms often are critically important and define the laboratory tests performed. Common symptoms:
- Intense pain
- Abdominal pain/cramping
- Blood in stool
- Loose stools
- Reduced appetite
Upon clinical examination, physicians may find:
- Extra-intestinal involvement
- Intestinal obstruction
- Abscess formation
- Fistulae or obstructive connections between tissues
- Strictures or narrowing of the bowel
- Eye inflammation
- Skin disorders
- Inflammation of liver bile ducts
- Delayed growth in children
Crohn’s Disease Activity Index (CDAI) is a simple screening test which uses a point system to score and quantify symptoms in Crohn’s patients. Diagnosis is confirmed with histopathological tests, immunohistochemical tests, molecular biology, manual examination by colonoscopy, and tissue biopsy.
Gene expression – genetic profiles can differentiate Crohn’s patients from non-inflammatory diarrheal disorders.
Samples – blood tests and urine tests, and stool specimens are collected to look for anemia, inflammation, or malnutrition. An ESR, or sed rate test or C-reactive protein (CRP) blood test may be conducted.
Imaging – Cross-sectional radiographic imaging is favored due to its ability to assess the entire bowel, fistulas and abscesses. Some tests use a pharmacologic anti-peristaltic agent (a liquid to drink before the test) to improve subjective image quality. Some say the agent is not diagnostically necessary, complicates exam protocol and increases expense.
- X-ray – provides an image of obstructions in the abdomen.
- Endoscopic examinations – a thin, flexible imaging instrument called an endoscope.
- Sigmoidoscopy – a lighted viewing instrument which can only reach the last part of the colon.
- Colonoscopy – used to examine the entire colon; the preferred test.
- Upper gastrointestinal (UGI) – a video monitor displays the images of continuous X-rays (fluoroscopy) taken to track the movement of a liquid agent through the esophagus, stomach, and the small intestine.
- Barium enema – fluoroscopy with a barium agent to examine the large intestine (colon).
- Computed tomography (CT) scan – looks specifically at the small intestine for signs of Crohn’s disease.
- Magnetic resonance imaging (MRI) – pictures of the organs produced with a magnetic field and pulses of radio wave.
- MR Enterography (MRE) – considered now to be the 1st test to order as it reduces the patient’s exposure to ionizing radiation, and has high diagnostic confidence.
- Confocal Laser Endomicroscope (CLE) – uses a florescent dye to view the bacteria at a sub-cellular level within the mucous membrane of the gut.
- Double-Balloon Enteroscopy (DBE) – uses carbon dioxide rather than regular air to fill the intestine, as standard endoscopic procedures cannot reach parts of the small intestine.
Biopsy – an invasive procedure to take tissue samples from the affected areas identified by sigmoidoscopy or colonoscopy. This procedure is used to confirm the diagnosis of Crohn’s disease, and to find out whether a tumor or cancer is present.
Pulmonary – tests of pulmonary or lung function test may find abnormalities without invasive diagnostic procedures as Crohn’s patients often have pulmonary abnormalities.
Home genetic tests – Direct-to-consumer (DTC) genetic tests often give inaccurate predictions of disease, overstate the risk, and may pose ethical problems considering the lack of genetic counseling provided. Patients interpret the results on their own and are often confused by them. Genetic results are often difficult to interpret, even for medical professionals.
Crohn’s Disease Treatment
Treatment goals are to provide symptom relief, induce and maintain remission. Long-term management seeks to prevent relapse, recurrence and complications. Traditional “step-up” therapy seeks to do the most with the least effective required dose. Treatment is approached first with immunomodulators and corticosteroids. Most CD patients eventually require surgery.
“Top-down” treatment is early aggressive therapy that is proposed to yield better outcomes and goes beyond symptom relief. Intestinal healing and mucosal healing is a new goal of therapy by using new biological agents to stimulate the innate immune system. Intervening early with aggressive treatment has the potential to enhance customized individual treatment.
Medications to induce and maintain remission and prevent relapse may provide symptom relief but also may be associated with rare but serious side effects, including infections and lymphoma. Medication seeks to control the inflammation and reduce the probability of relapse. Treatment depends on the effect of the disease on the patient and the severity of the disease.
Aminosalicylates – 5-ASA or mild, maintenance drugs.
Immunomodulators – azathioprine (Imuran), 6-MP, ciclosporin (Neoral), and methotrexate can have fast-acting and long-lasting benefits of healing fistulas and reducing the need for steroids, hospitalization and surgery.
Corticosteroids – tablets, enemas or suppositories to reduce inflammation in acute mild to moderate disease. Long-term use can be detrimental as they improve symptoms but may not induce healing.
- Budesonide – a synthetic steroid with anti-inflammatory value.
- Antibiotics – metronidazole, ampicillin, ciprofloxin and others may reduce inflammation and stop infection.
- Biologic therapy – monoclonal antibodies are antagonists of tumor necrosis factor, an important cause of inflammation.
- Infliximab (Remicade) is used for severe disease not improved by corticosteroids or immunosuppressants. Administration after surgery stops intestinal inflammation for up to three years. Symptoms return without maintenance therapy, however, lowering the dose of infliximab may effective.
- Certolizumab Pegol – brand name Cimzia, maintains remission of Crohn’s disease for up to 18 months. Non-interrupted therapy is best to retain remission.
- Adalimumab – another biological agent, however the drug transfers in utero. Placental transfer retains the drug in a newborn’s bloodstream for at least three months, however, the mother’s health takes precedence and stopping treatment may be more harmful than the potential risks to the infant later in life.
- Opioid receptor antagonist – Naltrexone, named Revia and Depade, interferes with an opioid receptor. This may lead to the reversal of the inflammation as endorphins and enkephalins have a role in inflammatory process.
- Two-Drug Combo – combination therapy with infliximab and azathioprine achieved steroid-free remission after 26 weeks in 57 percent of patients. 44 percent of patients achieved remission with infliximab alone and 30 percent with azathioprine alone.
- Vitamin supplements – can be used alone or in combination with drugs to restore vitamin sufficiency.
- Diarrhea medicines – to treat diarrhea however, they are often ineffective and can have serious side effects.
Four out of five Crohn’s patients will need some kind of surgery at some point during their lifespan, with no increased factors for gender, race or family history of inflammatory bowel disease. Advanced, minimally invasive surgery is attempted first, but the disease can pop up somewhere else. Increased risk for bowel surgery is found in older patients and greater disease severity. Post-surgical Crohn’s disease happens often with 34 percent needing surgery one year after with as many as 47 percent needing surgery five years later.
Types of Surgery
- Fistula Plugs – a surgical anal plug is placed over the fistula, which was causing intestinal contents to spill from the anal canal, preventing systemic infection.
- Strictureplasty – restructures the intestine instead of removing and shortening whole sections. This technique widens the bowel to allow intestinal contents to safely pass through.
- Laparoscopic Surgery – small incisions leave little outside scarring, reduce internal scarring and adhesions but take longer to perform.
Cellular Therapy and Regenerative Medicine
Healthy stem cells from a patient’s own bone marrow can regenerate small pieces of intestine in the lab. The researchers hope to grow larger pieces to produce enough tissue to replace damaged intestines. The same procedure is done in bone-morrow transplants to cure leukemia or myeloma.
The procedure is conducted in six phases over two months:
- Initial Chemotherapy (Cyclophosphamide + G-CSF) – immune-system cells are reduced in the blood of the patient.
- Migration of Stem-Cells to the Blood – the system reacts by releasing stem cells from the bone marrow into the blood.
- Collection of Stem Cells by means of Apheresis – the stem cells are separated and collected.
- Cryopreservation of Stem Cells – the cells are frozen and preserved.
- Second Chemotherapy – complete voiding of immune system cells, leukocytes, to provide a blank slate for new cells.
- Autologous Stem-Cell Transplant – stem cells are transplanted and the system is reset leading to remission of Crohn’s disease.
- Parasites – introduction of worms increases or restores mucus production in the colon, providing symptomatic relief, however the worms can cause harm and damage the gut, exacerbating bowel inflammation.
- Microbes – Transplantation of microbes from a healthy donor introduce new species in the intestinal microbial colonies and restores balance.
Granulocyte and monocyte adsorption apheresis (GMA)
A medical device containing cellulose acetate beads filters the granulocytes and monocytes/macrophage known to promote inflammatory bowel disease. Blood is removed from one arm and passed through the device. The beads remove the granulocytes and monocytes/macrophages and the blood is given back to the patient through the other arm.
Dietary factors in Crohn’s disease involve relationships with folate, calcium, vitamin D, red meat, refined sugar and fats. Fruits, vegetables, fiber and dairy are associated with the expression of inflammatory bowel diseases. Identifying dietary factors can be equally effective as medications for mucosal healing.
When the intestines are inflamed, absorption of nutrients may be diminished. Appetite may be insufficient due to pain and irritation. Thus, a double problem presents itself. Not enough food is being consumed and that which is ingested, is not bioavailable due to absorption problems. Immune system functioning depends on the adequate intake and absorption of proteins, fats, calories, vitamins, and minerals. Growing and building new cells and tissues becomes a critical problem for those with Crohn’s disease.
Children and teenagers don’t often have the education or the language to express their experiences. They might just know that they feel bad and don’t feel like eating. They also may be picky eaters anyway or have particular food choices which limit their options. Also, nutritionally empty packaged foods may be readily available and become their food of choice. They face peer judgment and may be reluctant to choose differently from their friends. Proper nutrition is vital in the growing years to promote life-long health.
- Dairy products have been perceived as having the potential to cause adverse effects in individuals with Crohn’s disease (CD) and are often avoided, potentially increasing the risk of osteoporosis and related morbidity associated with inadequate dietary calcium intake. Dairy products had no effect on self-reported CD symptoms for most people. Dairy products with a high fat content were most frequently reported to worsen perceived CD symptoms.
- Fatty acids from fish oil, prebiotics, and antioxidants have anti-inflammatory benefits and can improve quality of life in CD patients.
- Elemental diets consisting of liquid shakes with protein and supplements may aid people struggling with proper nutrition. These liquid diets can give the digestive system a rest while supplying basic or elemental nutrition needs.
- For severe cases of malnutrition, hospitalization may be required. Total parenteral nutrition (TPN) is administered directly into the bloodstream through a feeding tube.
Probiotics appear to down-regulate production of immune system proteins that cause inflammation. Intestinal bacteria probiotics can enhance the production of functional immune cells and regulatory T-cells. The intestine can rebalance and stop invading cells and infection. Probiotics can be found in powder form to add to nutritional shakes. They are added to orange juice and yogurt, among others.
Complimentary alternative medicine often employs analgesic use including cannabis use. This practice is common for symptom relief of chronic abdominal pain. Those with a history of abdominal surgery and/or a low quality of life index tend to use cannabis more and/or be more open to the use of cannabis.
Integrative treatment of chronically ill patients considers the psychological factors that CD poses in a stressful life position. Coping with any health-related problems can lead to low negative emotions (sadness, anger) expressiveness. Patients work to express emotions, be more assertive and less agreeable. Self-image constructs are improved to improve the quality of life.
Narcotics use is not advised as it complicates treatment. Disease severity and duration may increase and lead to further surgeries. Narcotics are still widely employed however, especially in hospital situations. Researchers discourage the practice.
Aspirin use is not advised as a strong positive association between regular aspirin use and CD has been demonstrated. Aspirin has a negative effect on gastrointestinal tract mucosa and may induce inflammatory bowel disease, especially Crohn’s disease.
Fructose intolerance is shown to be factor in CD. Intolerance is diagnosed by exclusion or with a breath hydrogen test. A healthy nutritional balance is complicated as high fructose corn syrup is found in many packaged foods.
Banana Plantain Fibers
Fibers found in plaintain based foods may block inflammation in the gut. These soluble fibers prevent the uptake and transport of E. Coli across gatekeeper cells. Tests are continuing to find other foods to stop the harmful effects of low fiber and processed foods.
Some fruits such as pomegranate, raspberries and nuts have naturally occurring polyphenol, a benefical ellagic acid. Administration of ellagic acid increased mucosal cell production and decreased inflammatory proteins. Damage and oxidative stress was also reduced.
Current blood tests for B12, a critical vitamin, have accuracy and sensitivity problems. A new breath test is a non-invasive and sensitive test to detect vitamin B12. FDA approval is the next step.
Analysis of fecal matter with gas chromatography-and biomarkers of RNA can revealed patterns associated with CD. These new types of analysis are rapid, non-invasive assessment of microflora, bacteria and/or the epithelium in disease states.
Differentiating inflammation from fibrotic bowel wall changes is made easier now with Transcutaneous Ultrasound Elasticity Imaging (UEI). This noninvasive procedure measures tissue mechanical properties to distinguish between unaffected tissue, tissue that is inflamed and tissue with fibrosis.
Drug delivery may be improved with nanoparticle coating of pharmacologic drugs. Current systems use a coating of a polymer shell on drug molecules. Targeting of absorption by the lower intestine is difficult as medication is affected by stomach acidity and uptake by cells higher up the gastrointestinal tract. Particle engineering techniques include spray drying, antisolvent methods, dialysis methods, emulsion methods and cryogenic methods.
- Ulcerative colitis – inflammation of the large intestine, causing ulceration and bleeding.
- Ankylosing spondylitis – inflammation affecting the spine and joints.
- Erythema nodosum – inflammation in the skin and underlying tissues.
- Nephrolithiasis – kidney stones, tissues made of small crystals.
- Sclerosing cholangitis – blockages to the bile drainage system in the liver or outside of it.
- Diverticular disease – pockets/out-pouching in the wall of the large bowel (colon).
- Endometriosis – tissue normally lining the uterus grows on other organs like the bowel and bladder.
Crohn’s disease is increasing worldwide, especially in developed countries. Several factors can cause CD along with other intestinal related disorders. Genetic susceptibility is a major factor with inflammation of the bowels seen in families. The genes, however, may predispose a person to Crohn’s disease but environmental factors may trigger it.
Environmental factors include lack of interaction with helpful bacteria in the environment due to better sanitation and the shift to office work. Dietary changes in the modern environment include a preponderance of packaged foods with high fructose corn syrup, high fat and high sugar foods. Stress may play a part, initiating harmful immune suppression.
Treatment is moving away from providing not just symptom relief but also actually healing of the affected areas. New treatments to initiate helpful immune events and dampen harmful ones are seeing results. Cell engineering and alternative treatments may hold promise for a cure. For now though, no cause is known and no cure has been found.