CROHN'S DISEASE

EPIDEMIOLOGY AND GENETICS

• Epidemiology
• Genetic Predispositions
• Environmental Factors

Epidemiology

Crohn's disease is a long-term, chronic disorder of the intestine, for which there is no cure.6 The etiology (underlying cause) is unknown. In persons who have Crohn's disease, the gastrointestinal tract becomes inflamed and weak; making digestion difficult, leading to general physical debility. In the United States, the annual incidence of the disease is about two out of 100,000 persons. Crohn's disease is diagnosed in people in their 20s and 30s, but occurs in infants and children. More common in women, Crohn's disease is rare in Asians or Africans living outside the U.S.7-9 Half of patients with Crohn’s disease require surgical treatment within ten years; 1 in 12 require 1-2 operations during this period.10

Genetic Predisposition

The incidence of Crohn's disease is increasing in the West, suggesting lifestyle factors are a cause. “Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin,”11 and it develops in twins and siblings at a much higher rate.12,13 Both genetic and microbial factors play a pivotal role in Crohn's disease.

Studies have found a gene that may be susceptible to inflammatory bowel disease on chromosome 16 (CARD15).4,14 Crohn’s disease may be caused by an abnormal immune response to enteric bacteria, resulting in excessive inflammation in genetically susceptible individuals.4,15

Environmental Factors

A diet high in fat or refined foods may be a factor in Crohn’s disease. Patients with Crohn's disease show increased consumption of refined sugar which can adversely affect the beneficial microflora of the intestinal system.16 Studies support links between Crohn’s disease and other environmental factors including: geographical location, social and economic status, drugs, smoking, stress, microbial agents, and appendectomy.17 Studies show that exposure to bacterial agents early in life contribute to development of Crohn’s disease.18

ETIOLOGY AND MECHANISMS OF ACTION

In the healthy intestine, enteric microflora are present and necessary. Between one billion and one trillion normal intestinal bacteria exist in every gram of intestinal content. Healthy bacteria contribute to digestion and keep abnormal bacteria, which can enter the GI tract in food and water from surviving and causing illness.19 Although the etiology of Crohn's disease is obscure, harmful antigens may activate immune cells in the intestinal wall, causing inflammation.20,21 These antigens may come from dietary peptides found in wheat, rye, and barley,22 so elimination of these dietary foods leads to remission. Harmful antigens cause immune cells to secrete pro-inflammatory agents (cytokines), such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1b (IL-1b), that promote an inflammatory response.23 Inflammation impairs the normal intestinal barrier and increases permeability to harmful antigens.24 Because a large percentage of immune cells reside in the gastrointestinal tract, activation of these cells can cause gastrointestinal symptoms.

Crohn's disease can attack any part of the digestive system from the mouth25 to the anus, but commonly affects the ileum (lower portion of the small intestine) or the colon (large intestine). The most common complication is blockage of the intestine. Blockage occurs because the disease thickens the intestinal wall through swelling and scar tissue; narrowing the passage. Crohn's disease causes ulcers that tunnel through the affected area into surrounding tissues such as the bladder,26 vagina,27 or skin.28

Nutritional complications are common in Crohn's disease. Deficiencies of protein, calories, and vitamins, particularly vitamin D, are well-documented.29-32 These deficiencies may be caused by inadequate dietary intake, allergic reactions, intestinal loss of protein, or poor absorption.19,33-36 Osteoporosis is another common complication occurring with Inflammatory Bowel Disease (IBS) and people with Crohn’s disease are at increased risk.37-39

ANATOMY AND PHYSIOLOGY (Structure and Function)

The digestive system is made up of the digestive tract; consisting of a long tube of organs that run from the mouth to the anus, including the esophagus, stomach, small intestine, and large intestine; together with the liver, gall bladder, and pancreas; which produce important secretions for digestion that drain into the small intestine. The digestive tract in an adult is about 30 feet long.4

The colon can be functionally divided through the transverse colon into two parts, the right and left colon. The right colon (cecum and ascending colon) plays a major role in water and electrolyte absorption and fermentation of undigested sugars, and the left colon (descending colon, sigmoid colon and rectum) is predominantly involved in storage and evacuation of stool.4

A colon lining that is moist and healthy affects the regularity and health of the colon in a number of ways:

• Delicate nerve endings that extend down into the colon wall are protected. Neural messages between the brain and colon can be reliably transmitted. This promotes regularity.
• Healthy intestinal microflora are able to flourish. These bacteria breakdown waste and create additional lubrication; promoting regularity. Healthy intestinal bacteria breakdown waste, cleans the colon, and protects it from infection.
• Movement of fluids into and out of the epithelial cells in the colon wall is more efficient.
• Nutritional uptake of vitamins and electrolytes is optimized.
• Stool passage through the colon is easier; optimizing colon function and promoting regularity.4

The colon is designed to perform three major tasks:

• Absorption of water and vitamins. The colon facilitates absorption of water and vitamins that have not already been digested. The colon absorbs sodium, potassium, acids, gases, some short-chain fatty acids created from the metabolism of plant fibers and undigested starch, and vitamins synthesized by bacteria (especially, biotin and vitamin K).
• Formation of waste products into feces. The colon will eliminate the waste from the body. The colon moves the waste, toxins, carcinogens, and pollutants out of the body.4

A healthy GI tract contains nearly sixty varieties of bacteria or microflora which aid digestion, promote the synthesis of vital nutrients, maintain proper pH (acid-base) balance, and keep harmful bacteria in check. The mucosa, or surface cell layer lining the intestines, allows for the passage of nutrients into the bloodstream, secretes hormones and lubricants, and prevents absorption of toxins. Approximately 15 contractive movements occur in the colon per minute. This peristalsis moves food through the intestinal tract, maximizes absorption of liquids and nutrients, while eliminating the stool. Regular bowel movement prevents buildup of toxic substances that result from putrefaction and excessive fermentation.4

PATHOPHYSIOLOGY

• Symptoms
• Possible Causes
• Diagnosis
• Blood Tests
• Other Risk Factors for Patients with Crohn’s Disease

Crohn’s disease is a lifelong ailment that can be controlled, but there is no cure or even a definitive cause. Patients experience excruciating attacks of abdominal pain and diarrhea followed by weeks, months, or even years of remission.40 Development of abscesses (puss filled pockets of infection) or fistulas (abnormal connecting channels) occurs. Fistulas may form between two different parts of the intestine, or connect the intestine and bladder, or the intestine and the skin surface, especially around the anus. Fistulas formed between the colon and small intestine or stomach result in bacterial overgrowth causing diarrhea, weight loss, and malnutrition.4 Surgery may be required to close fistulas.41 Over one third of patients with Crohn’s disease develop perianal disease involving anal fissures, peri-anal abscesses, and fistulas. These symptoms seldom respond well to conventional therapies.4,42

Symptoms

The following are the most prevalent symptoms of Crohn's disease:

• Severe abdominal pain and diarrhea that is occasionally mixed with blood. Unlike ulcerative colitis, in which patients may have episodes of diarrhea as often as 10-15 times a day, people with Crohn's may have fewer episodes, although each episode may be extraordinarily painful.
• Cramps or pain after eating, especially in the lower right side of the abdomen.
• Chronic low-grade fever, loss of appetite, fatigue or weight loss, especially if accompanied by persistent nausea and vomiting.
• Arthritic symptoms or sudden worsening of existing arthritic symptoms in the arms and legs.
• In young children, any of the above mentioned symptoms, plus failure to thrive; in older children, failure to grow at a normal rate.
• Anemia.

Possible Causes

Cytokines

T-cells regulate intestinal immune responses and the pathogenesis of Crohn's disease. They stimulate secretion of cytokines (of the Th-2 type).43 Cytokines are cause development and activation of immune cells that control the inflammatory response.4,44 Antigens from food and bacteria in the gut are continually in contact with the intestinal mucosa. The action of cytokines secreted by T-cells prevents cell-mediated immune responses to these antigens. In Crohn's disease, there is a shift toward pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha).45

Neutrophil Dysfunction

Bone marrow is implicated in the genesis of Crohn's disease. Instead of Crohn's disease being considered a disease of primary intestinal dysfunction, it may be a consequence of an interaction between bone marrow constituents and intestinal factors.46 While the progression from neutrophil dysfunction to the generation of Crohn's disease is speculative, a common pathway has been observed in neutrophil disorders associated with Crohn's disease.47,48 Neutrophils function as a first-line defense when microbes invade the mucosal lining of the intestine. Neutrophils mediate rapid clearance of mucosal microbes. If the neutrophils are dysfunctional, monocyte-macrophages are recruited and activated; triggering lymphocyte activation of T cells. Neutrophils and macrophages produce pro-inflammatory cytokines, including tumor-necrosis factor alpha (TNF-alpha), which contributes to inflammation. Anti-TNF therapy has been successful but does not address the underlying etiology of the disease.49,50 The impairment of neutrophil function may result from a combination of genetic and environmental influences.

Diagnosis

Crohn's disease can usually be diagnosed. It is difficult to distinguish Crohn's disease from ulcerative colitis; therefore physicians employ more than one diagnostic method. Common diagnostic tools include:

• X-rays of the large and small intestines
• Sigmoidoscopy
• Colonoscopy, usually including tissue biopsy
• Barium enema.51,52

Blood Tests

Routine blood tests for liver function and iron levels, and other blood tests, may be ordered to ensure that other health conditions do not interfere with the healing process. Blood tests check for anemia, which could indicate bleeding in the intestines, or uncover a high white blood cell count, which is a sign of inflammation. Testing of a stool sample can determine if there is bleeding or infection in the intestines.

The American Society of Gastroenterologists has provided the following guidelines for gauging the severity of Crohn's disease:

• Mild-moderate Crohn's disease applies to ambulatory patients who are able to tolerate food by mouth without dehydration, high fevers, rigors, prostration, abdominal tenderness, painful mass, obstruction, or over 10% weight loss.
• Moderate-severe disease applies to patients failing to respond to treatment for mild-moderate disease or those with more prominent fever, weight loss, abdominal pain or tenderness, intermittent nausea or vomiting, or anemia.
• Severe-fulminant disease applies to patients with persisting symptoms despite the introduction of steroids or individuals with high fever, persistent vomiting, intestinal obstruction, rebound tenderness, cachexia, or an abscess.

Remission refers to patients who are asymptomatic or without inflammatory sequelae. This includes patients responding to medical intervention or undergoing surgical resection without evidence of residual disease. Patients requiring steroids to maintain their well being are "steroid-dependent" and are not "in remission".53,54

Other Risk Factors for Patients with Crohn’s Disease

• Increased risk of gallstones, especially in ileal disease or after ileal resection. Alterations in enterohepatic (gut-liver) bilirubin cycling results in increased bilirubin levels in the bile; leading to pigment rather than cholesterol gallstones.55
• Stiffness and arthritic-like symptoms in the joints from inflammation. The back is commonly affected.56 Patients are at risk for clubbing (abnormal thickening and widening at the ends of fingers and toes).57,58
• Psoriasis – a chronic skin disease marked by periodic flare-ups of sharply defined red patches covered by a silvery, flaky skin.59
• Inflammation in parts of the eye. People with arthritic complications have eye problems.60
• Anemia - internal blood loss from ulcers is a problem because of impaired ability to absorb vitamins and minerals for blood production.61
• Canker sores and mouth yeast infections are common, and often persistent.62
• Osteoporosis is a common complication of inflammatory bowel disease, and people with Crohn's disease are at particular risk.63,64
• Crohn’s disease affects women differently, causing early menopause and menstrual abnormalities, including premenstrual disorder, abnormal bleeding, and pain65,66

ENDOCRINOLOGY AND BIOCHEMISTRY (REGULATION AND METABOLISM)

• Biochemistry of Crohn’s Disease
• Biochemistry of Supplements

Biochemistry of Crohn’s Disease

An inflamed intestine is less able to fully absorb and digest nutrients. Depending on how severely the small intestine has been injured by inflammation, vital nutrients and unabsorbed bile salts may travel into the large intestine. This is why many patients don’t have an appetite and are malnourished.67,68

When the colon is unable to function efficiently, an accumulation of toxins can build up in the lymph, bloodstream, and intestines; leading to deterioration of nerve fibers in the lining of the digestive tract.69 The ileum (lower end of the small intestine) is the major area for intestinal absorption of bile acids secreted in the bile by the liver into the duodenum (upper end). Bile acids transport and absorb fats. An inflamed ileum impairs absorption of vitamin B12 and bile salts. Bile acids that are not absorbed by the ileum, pass into the colon; inducing the colon to secrete liquid, causing diarrhea. If the bile acids are not absorbed in the colon, a consequent deficiency causes fat malabsorption and diarrhea.70 Long term, reduced absorption of nutrients causes problems such as anemia, weight loss, and impaired growth and development (in children).

Patients often have a fewer beneficial microflora. Probiotic therapy induces and maintains remission by reducing inflammation and by fighting yeast or bacterial infections.71,72

Selenium functions as an antioxidant, neutralizing hydrogen peroxide that can damage cell membranes. It assists in the synthesis of protein. Selenium deficiency is common in Crohn’s disease.73,74 Supplementation may alleviate this problem.

Some of the damage in Crohn’s disease is caused by free radicals; molecules produced during fat metabolism, stress, and infection. Free radicals cause inflammation.75,76 Many sufferers are deficient in free-radical scavengers such as beta-carotene, C, E, zinc, and selenium.77-79

Vitamin C (ascorbic acid) can cause a pro-oxidant effect and aggravates inflammation of the colon.80 A lower than required intake of iron increases the risk of Crohn’s disease.81

Colon and bowel malfunctions are big factors in accelerated aging. Telomeres are sequences of DNA on the end of chromosomes that regulate chromosome activity. Each time a cell divides, telomeres shorten until they are so short that cellular division no longer continues. Greater telomere length reductions occur in Crohn’s disease.82

Biochemistry of Supplements

Antioxidants

Intestinal inflammation is accompanied by excessive production of reactive oxygen and nitrogen metabolites. To counteract their harmful effects, the intestinal mucosa contains an extensive system of antioxidants. The levels and the balance of important antioxidants are impaired within intestinal mucosa during inflammatory bowel disease.83

Butyrate

Butyric acid (also known as butyrate) is a short chain fatty acid produced when intestinal fiber is metabolized by bacteria. Butyrate ameliorates inflammation in ulcerative colitis and Crohn’s disease, but the mechanism is not known. Pro-inflammatory cytokines, including IFN-gamma, are important in the pathogenesis of inflammatory bowel disease, and abnormal activity of STAT1 is associated with human malignancies and intestinal inflammatory diseases. Butyrate strongly inhibits signaling by IFN-gamma. This short chain fatty acid inhibits IFN-gamma-induced tyrosine and serine phosphorylation of STAT1,84 which is probably important during inflammation. Pro-inflammatory cytokines are key in the pathogenesis of Crohn's disease. Activation of nuclear factor kappa B, which is involved in gene transcription that increases cytokines, is elevated in the intestinal mucosa of sufferers. Butyrate decreases TNF production and pro-inflammatory cytokine mRNA expression in Crohn’s patients.85

Glutamine

Glutamine is a major fuel and an important nitrogen source for the small intestinal cell. It maintains mucosal cell integrity and the gut barrier. Increased gut permeability may be a factor in the pathogenesis of Crohn's disease. Although some reports have indicated that glutamine is an important therapeutic alternative in the management of inflammatory bowel diseases (IBDs), other studies have not shown the benefit of a glutamine-enriched diet.86 Glutamine promotes healing in Crohn’s disease.87

Selenium

Selenium is a potent antioxidant necessary for calcium and vitamin C metabolism, conversion of blood sugar into energy, reduction of platelet aggregation, and promotion of cardiovascular health. Reduced free radical scavenging as a result of selenium deficiency may contribute to the inflammatory process of IBD. The recommendation for supplementation with selenium is supported.88

Folate

Folate produces and maintains cells, especially during periods of rapid cell turnover as is the case for red blood and GI cells, because it is needed to make DNA and RNA. Folate is essential for metabolism of homocysteine; maintaining normal levels of this amino acid. Sulfasalazine (used to control Crohn's disease) interferes with folate utilization.89 A deficiency of folate, vitamin B12 or vitamin B6 may increase blood levels of homocysteine, and folate supplementation decreases homocysteine levels; improving endothelial function in the GI tract.90

DHEA

Studies link low levels of DHEA to aging and disease. A deficiency of DHEA correlates with chronic inflammation. Inflammatory cytokines [TNF-alpha, IL-6, IL-1 (b), LTB(4)] are measured by a laboratory cytokine blood profile. DHEA lowers these pro-inflammatory cytokines. The deficiency of DHEA in inflammatory diseases implies a deficiency of sex hormones for which DHEA is a precursor.91 Sex hormones have beneficial effects on muscle, bone, and blood vessels, however, mainstream therapy for Crohn’s disease with corticosteroids lowers androgen levels. Researchers argue that hormone replacement for chronic inflammatory diseases should include corticosteroids and DHEA.91 DHEA boosts beneficial interleukin-2 (IL-2) and suppresses damaging interleukin-6 (IL-6) levels. IL-6 is overproduced in the elderly; contributing to autoimmune disease, immune dysfunction, and osteoporosis.92 Corticosteroids are similar to cortisol, a steroid produced in the adrenal gland. Corticosteroids reduce inflammation. Because of the side effects (e.g. Cushing’s Syndrome) corticosteroids are given in the lowest possible dosage for the shortest amount of time.

Probiotics

With more than 400 microorganism species in the human GI tract, the overall balance can profoundly influence gut health. Intestinal bacteria produce toxins and antitoxins, alter chemical composition of foods and drugs, produce and degrade vitamins, degrade dietary toxins, and inhibit the growth of certain pathogens. Gut-derived products play a role in the systemic immune inflammatory response.19 Several probiotic mechanisms of action, relevant to IBD, have been elucidated: (1) probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium; (2) probiotics stimulate immune responses of gut-associated lymphoid and epithelial cells; (3) probiotics have antimicrobial activity and suppress pathogen growth; and (4) probiotics enhance barrier function.93

CROHN'S DISEASE

PHARMACOLOGY

• Anti-Inflammatory Agents
• Steroids
• Monoclonal Antibodies
• Immunosuppresion
• Total Parenteral Nutrition
• Surgery
• Growth Hormone Therapy

Crohn's disease is not curable. Depending on severity of the symptoms, medical treatment involves a three-pronged approach to controlling the disease: First, drug therapy and a restricted diet; then if necessary, hospital treatment; and the last resort is surgery.94 Because there is no cure, steps are taken to avoid recurring attacks. In active disease, achieving remission is pursued as quickly as possible. Some patients require maintenance medications when there are no symptoms. Children with Crohn's disease may require high-protein, high-calorie liquid supplements to maintain growth because the disease is devastating in children.95

Anti-Inflammatory Agents

Aminosalicylates, such as sulfasalazine, mesalamine, Asacol®, Pentasa®, and Rowasa®, are intestinal anti-inflammatory agents that are the cornerstone of conventional medical treatment. These drugs may be prescribed for years without interruption.96,97 Aminosalicylates are given orally or as suppositories. They interrupt inflammation; diminishing symptoms of diarrhea, bleeding, and abdominal pain. Many are allergic to aminosalicylates, as manifested by vomiting and headaches.98

Steroids

In active Crohn's disease, steroids such as prednisone are commonly prescribed alone or with aminosalicylates to reduce intestinal inflammation.99 Steroid use can be problematic because of severe long-term side effects including:

• Cushing's Syndrome
• Muscle disorders
• Hair loss
• Weight gain
• Immune system suppression
• Osteoporosis
• Hypertension
• Hormone imbalance

Even with these risks, steroids are often used during the acute stage to get symptoms under control.100 Prednisone mimics the effects of the body's natural corticosteroid hormones by suppressing the release of inflammatory cytokines and blocking production of prostanoids. Once under control, aminosalicylates are for maintenance therapy. Tapered use steroids is a critical time during disease treatment when many patients find themselves precariously trying to remain in remission while weaning themselves from steroids.101

To reduce the need for steroids, immunosuppressants such as azathioprine, 6-mercaptopurine, or cyclosporine may be substituted.102,103 Various chemotherapy agents and organ transplant anti-rejection drugs are used.104,105 These medications have their own side effects. Antidiarrheal agents may be taken for mild bouts of diarrhea, and antispasmodics for cramping. When patients have arthritis-like symptoms, anti-arthritic medications are taken. In severe disease, patients require a bland, well-balanced diet.106

Monoclonal Antibodies

A new treatment (1995) with a monoclonal antibody known as infliximab (Remicade®) was successfully used when other conventional treatments failed.107,108 Infliximab is a genetically engineered antibody that reduces intestinal inflammation caused by TNF-alpha and by destroying TNF-alpha-producing cells. This treatment is extremely effective in patients resistant to other treatment, even steroids. Remission is up to 80% when it is used with improvement at 4 weeks after 5 mg/kg. More than 50% achieved clinical remission,109,110 fistulas healed quickly. Infliximab decreases levels of serum IL-6 and C-reactive protein.111 Elevated concentrations of TNF-alpha are found in stools from Crohn's disease patients and correlate with disease activity. Infliximab reduces infiltration of inflammatory cells and production of TNF-alpha. GM-CSF levels (which precede increasing white cells) and mucosal histology (cell) scores decrease after three infliximab infusions, as do white blood cell counts. Infliximab inhibited in vitro T cell GM-CSF production.112 Re-treatment with infliximab is necessary to prevent relapse and long-term side effects are unknown. Initially there can be severe side effects, including transfusion-type reactions, because Infliximab is an antibody (foreign protein) given intravenously.113 Infliximab is associated with delayed hypersensitivity (serum sickness-like) reactions, particularly after prolonged intervals (>12 weeks) subsequent to an initial treatment. The use of this drug requires long-term planning due to the requirement for repeated infusions.114-117

Immunosuppresion

Treatment for Crohn's disease entails immunosuppression. Inherited disorders of immunity often lead to a Crohn's-like disease.118 Trials with granulocyte-macrophage colony-stimulating factor (GM-CSF) show promising results, the patients showed decreased Crohn's disease activity index (CDAI) scores during treatment. Re-treatment is effective and increased quality-of-life measures.119-121 GM-CSF is sold under the trade name Leukine® and restores immune function in cancer patients undergoing bone marrow-depleting chemotherapy.

Total Parenteral Nutrition

Severely ill patients with diarrhea and weight loss need intravenous nutrition in a hospital. This total parenteral nutrition (TPN) rests the intestinal tract. TPN is administered directly into the bloodstream by an infusion system. After stabilization, some patients require IV nutrition at home via a nursing service.122

Surgery

If Crohn's disease does not respond to treatment with drugs and diet, surgery may be recommended. Because Crohn's disease can affect the entire digestive tract, surgery removes only the severely inflamed part of the intestine. Surgery commonly involves the colon or small intestine. Occasionally, the end of the intestine that has been left in place will need to be brought to the skin's surface. When this procedure involves the small intestine, it is called an ileostomy. If the procedure involves the colon, it is called a colostomy. Although Crohn's disease may recur after surgery, the symptoms are likely to be less debilitating. When the disease recurs, it usually does so at the site of the last surgery.123,124

Growth Hormone Therapy

Growth hormone (GH) is the primary hormone responsible for growth in humans and regulates metabolic processes. The effects of GH are largely mediated via insulin-like growth factor 1 (IGF-1). Administering GH to patients with Crohn's disease may resolve symptoms.125,126 GH causes significant improvement in the number of liquid or very soft stools, severity of abdominal pain, and increases well being. Patients receiving GH who are on other medications are able to reduce their dosages.127-129

NUTRITIONAL THERAPY

• The 4-R Program

Because most medications for Crohn's disease have many of side effects, patients focus on nutrition and diet to stave off active disease or induce remission. Intolerance to certain foods and other nutritional factors play a role in management of Crohn's disease through nutritional modification.

Crohn's patients often consume high amounts of simple sugars at the time of diagnosis or following it.130,131 The propensity to consume simple carbohydrates indicates that many patients have not been counseled to reduce consumption of refined carbohydrates.132,133 Consumption of highly refined foods and sugars may be involved in the etiology.134,135

Nutritional management of Crohn's disease has the potential for a more beneficial role than methods using anti-inflammatories and steroids. An elemental diet can induce remission equal to, if not better than, prednisone.136-139 An elemental diet contains the essential elements of good nutrition, usually in liquid form with hypoallergenic protein contents. In patients already taking prednisone, the drug could be reduced or eliminated in 50% of patients following an elemental diet. While on an elemental diet, inflammatory parameters and intestinal permeability decrease.140,141

Because many Crohn's patients are often nutritionally deprived at diagnosis, using nutrition to induce remission provides an opportunity for the patient to become nutritionally replete, possibly for the first time in many years. Elemental diets used by practitioners are often unpalatable, however, detoxification programs exist for nutritional physicians that are palatable and introduce concentrated vitamins and minerals needed for recovery. The 4-R program for managing intestinal disorders stand for (1) remove, (2) replace, (3) reinoculate, and (4) repair.142

The 4-R Program

Remove: Remove all suspicious foods from the patient's diet that precipitate inflammation. The following are the most likely to be troublesome: dairy, eggs, nuts, fruit, tomatoes, corn, wheat or gluten, and red meat. All refined carbohydrates should be removed. All fats except for essential fatty acids should be eliminated because hard or trans fats are detrimental in Crohn's disease.143,144 Products such as Vivonex, UltraMaintain, or UltraClear can be used at the outset. UltraClear is preferable because it contains sufficient fiber to maintain regular bowel evacuation. Removal of gastrointestinal parasites, undesirable bacteria, or fungal elements is important. Remove yeast overgrowth by using an antifungal drug (e.g., oral nystatin).

Replace: Most patients are nutritionally imbalanced. Replacement of vital nutrients consists of a good multivitamin and mineral complex, together with minerals that are lacking. Minerals often lacking are iron, magnesium, selenium, and zinc. Vitamins most lacking are the B-complex vitamins, including folic acid, vitamin B6, and particularly vitamin B12, which is absorbed from the distal end portion of the small intestine.145 Deficiencies found in Crohn's disease are deficiencies of iron and calcium. Less frequently, deficiencies of zinc, protein, cyanocobalamin (B12), vitamin D, and folic acid are found.146,147 Patients exhibit oxidative stress and lower antioxidant vitamins. Vitamin E and C supplementation reduces oxidative stress.148 Long-term use of steroids warrants the inclusion of supplemental calcium and vitamin D to prevent osteoporosis caused by several factors: iron deficiency; vitamin B12 deficiency related to extensive disease of the terminal ileum; folate deficiency produced by anorexia and the consequently poor intake of dietary folate; or by inhibition of folate absorption by sulfasalazine, one of the common drugs used to reduce inflammation.149-151

Reinoculate: A normal healthy intestine contains about 5-7 lbs. of "friendly bacteria" responsible for manufacturing some vitamins and gut cell food. In a diseased intestine, these bacteria are out of balance or absent, having been replaced by pathogenic organisms or yeast overgrowth. Reinoculation consists of taking mixtures of Lactobacillus acidophilus and Lactobacillus bulgaricus with fructose oligosaccharides (FOS).152 L. bulgaricus is in Jerusalem artichoke and other vegetables. It is a substrate or food for the Lactobacillus species. Inhibition of pathogens by Lactobacilli follows the lowering of pH through liberation of acids, resulting in an antimicrobial action. Stool samples provide information regarding these overgrowth factors, pH, and the balance of fatty acids.

Repair: Frequently the lining of the small intestine becomes permeable; permitting antigens and other incompletely digested products to pass through the bowel wall. Repair of the protective layer consists of adding nutrients such as pantothenic acid (vitamin B5), zinc,153-156 fructose oligosaccharides, and vitamin C to build up the integrity of the intestinal wall itself. This can be done with oligo-antigenic products such as UltraSustain. Measuring intestinal permeability can indicate if a patient's GI function has recovered or if it continues to cause functional abnormalities in the body through the gastrointestinal lymphoid-associated tissue (GALT), where it increases release of pro-inflammatory mediators.

Patients who did not have their small bowel mucosal integrity restored (i.e., those who still had a "leaky gut"), relapsed (76-81%) within 1 year. Patients with normal gut mucosal integrity and healing had less than a 5% probability of relapse. The patients' GI mucosal integrity can be evaluated by lactulose/mannitol challenge.157 The effects of aging on intestinal permeability shows that intestinal permeability increases in later life.158

FUNCTIONAL AND PRACTICAL MEDICINE

Humans evolved by consuming a diet containing equal amounts of n-3 and n-6 (omega-3 and omega-6) essential fatty acids.159 Both the types of fatty acids in the diet affect the immune system by altering lymphocyte functions.160 Omega-3 fatty acids are found in nuts (especially walnuts), seeds, and fish oil; whereas omega-6 is generally found in animal fats, and in corn, sunflower seed, safflower seed, cottonseed, and soybean oil. Over the past 100-150 years, there has been an enormous increase in consumption of n-6 fatty acids due to increased intake of vegetable oils. In Western diets, the ratio of n-6 to n-3 fatty acids ranges from 20:1 to 30:1 instead of the traditional range of 2:1 to 4:1. High intake of n-6 fatty acids shifts the physiologic state to one that is more inflammatory by producing more inflammatory molecules from the prostaglandin E2 series. The products of n-3 fatty acids, prostaglandins of the E1 and E3 series, have more anti-inflammatory properties. The n-3 fatty acids may prevent coronary heart disease,161 hypertension,162 Type-II diabetes,163 ulcerative colitis,164 and Crohn's disease165 in some patients.

"Both the amount and type of dietary fat modulate intestinal immune function".166 Fats found in cold water fish oils, known as EPA and DHA, impact inflammation caused by Crohn's disease. Dietary oleic acid supplements cause an immunological reversal effect in the intestinal immune system in animals fed an elemental diet. Oleic acid is a C-18 fatty acid found in olive oil. Therefore, an excess of certain long-chain fatty acids in an elemental diet may negate its beneficial effect on gut-associated immune tissues (GALT). Linoleic acid, but not oleic acid, increased the production of IL-8 by HISM cells. Replacement of linoleic acid by oleic acid and increased intake of a diet rich in antioxidants could decrease inflammatory activity in Crohn's disease.167 Crohn's disease is associated with nutritional deficiencies, altered plasma concentrations of polyunsaturated fatty acids (PUFAs) and an anti-inflammatory response to fish oil that contains n-3 PUFAs.168

The fatty acid profile in Crohn's disease is associated with disease activity and serum antioxidant concentrations. The diminished antioxidant defenses in active and inactive Crohn's disease indicates that antioxidants should be considered in therapy. Serum concentrations of the antioxidants selenium, vitamin C, vitamin E, the activity of superoxide dismutase, and total antioxidant status were significantly increased after antioxidant supplementation of Crohn’s disease patients.169,170

Serum concentrations of beta-carotene, selenium, vitamin C, and the activity of glutathione peroxidase (GPx) were significantly lower before supplementation. After antioxidant supplementation, the levels of GPx increased. Supplementation with omega-3 essential fatty acids significantly decreased the proportion of arachidonic acid (an omega-6 essential fatty acid and pro-inflammatory prostaglandin precursor) and increased the proportion of EPA and DHA (omega-3 fatty acids) in fatty tissues.171

Arachidonic acid is an omega-6 fatty acid that produces excess inflammation by making the E2 series of prostaglandins. Supplementation with antioxidants improved antioxidant status in Crohn's disease in remission; indicating that an immunomodulating formula containing omega-3 fatty acids and/or antioxidants significantly benefited those with Crohn's disease.172 Fiber, starches, glutamine, and fish oils may all help with malnutrition in Crohn's patients.138

Men and women with Crohn's disease are at risk for osteoporosis, but the factors contributing to low bone-mineral density and its optimum treatment have not been established. The overall prevalence of IBD-associated osteoporosis is 15%, with higher rates seen in older and underweight subjects. The incidence of fracture is about 1 per 100 patient years, with fracture rates dramatically increasing with age.173 The recommendations in inflammatory bowel disease are similar to those for postmenopausal osteoporosis, with emphasis on lifestyle modification, vitamin D (400-800 IE daily), calcium (1000-1500 mg daily) supplementation, and hormone replacement therapy (estrogens/selective estrogen receptor modulators in women, testosterone in hypogonadal men). Bisphosphonates are approved for patients with osteoporosis (T-score < 2.5), osteoporotic fragility fractures, and patients receiving continuous steroid medication.174

Dehydroepiandrosterone (DHEA) functions as a prohormone in both estrogenic and androgenic families, acting as a precursor to many natural steroids with beneficial effects on muscle, bone, and blood vessels.175-177 DHEA can decrease the effects of chronic inflammation by lowering production of TNF-alpha and IL-6.178 DHEA-S (sulfate) deficiency may contribute to the bone loss of men with IBD with a commonly associated testosterone deficiency.179

In lupus, an autoimmune inflammatory disease, 200 mg daily of DHEA decreases the requirement for steroid therapy while improving symptoms.180 The immunomodulating properties of DHEA-S and its relationship to cortisol and chronic inflammatory bowel disease are underscored by low levels of DHEA combined with high levels of cortisol. Lower DHEA levels indicated an increase in IL-6 production related to the increased inflammation in Crohn's disease and ulcerative colitis.181 Patients with Crohn's disease may consider blood testing to determine baseline levels of DHEA so that they can discuss the appropriateness of adjunct therapy with DHEA with their physician.

Short-chain fatty acids (SCFA), such as butyric acid (butter) are produced by fermentation of water-soluble fiber by anaerobic bacteria in the large bowel.182 Fiber-rich diets decrease the risk of developing inflammatory bowel disease (IBD) and butyrate enemas are effective as a therapy in some patients. Crohn's disease involves an exaggerated T helper-1 (Th1) lymphocyte phenotype, characterized by production of IL-2 and interferon (IFN)-gamma that drives the inflammation. Butyrate significantly inhibits Th1-type responses.183 CD (intestinal) epithelial cells exhibit decreased oxidation of butyrate, down-regulation of oxidative pathway regulatory genes, and over-expression of mitochondrial (mt) genes.184 Pro-inflammatory cytokines, including IFN-gamma, play an important role in the pathogenesis of IBD, and abnormal activity of STAT1 is associated with human malignancies and intestinal inflammatory diseases. Butyrate is a strong inhibitor of signaling by IFN-gamma.185

SUMMARY

• Scientific Summary

Scientific Summary

Traditional treatments for Crohn's disease depend on the location and severity of disease, complications, and response to prior treatments. The goals of therapy are to control inflammation, correct nutritional deficiencies, and relieve symptoms like abdominal pain, diarrhea, and rectal bleeding. This may include drug therapy, nutrition supplementation, surgery, or a combination of approaches. Though treatment can help control the disease, there is no cure.

Crohn's disease is a debilitating disease of unknown etiology that attacks the gastrointestinal tract, making digestion difficult and leading to a wide variety of physical problems. Certain inflammatory agents called cytokines can result in an inflammatory cascade that produces thinning of the bowel wall, leading to scarring, thickness, abnormal bowel function, and malabsorption of nutrients. Crohn's disease is a lifelong, incurable condition that may move in and out of remission in patients. It presents with multiple complications, due to the disease process itself and due to the drug side effects. These drugs do not cure the disease, but they may induce remission.

Aminosalicylates that disrupt colonic inflammation are the first line of conventional treatment for Crohn's disease. Steroids are often administered during acute outbreaks. Chemotherapeutic agents are used in severe cases to eliminate badly diseased intestinal tissue. Intravenous administration of infliximab, an antibody with anti-inflammatory properties, has created remission in up to 80% of cases.

Dietary and nutritional management are important factors as a means to avoid food intolerance and provide necessary nutrients. An elemental diet, usually administered in a liquid form, has shown success at inducing remission138 Proprietary products such as UltraClear are often recommended to help detoxify the intestinal tract while providing concentrated amounts of necessary nutrients.

LIFE EXTENSION’S INTEGRATED PROTOCOL

• Supplement and Drug Recommendations

The most optimal approach for the overall management of the broad range of symptoms of Crohn’s disease is to utilize a range of nutritional therapies each of which addresses a specific type of problem related to the disease. The benefit of nutrient-based therapies is that they are free of serious side effects and can be used indefinitely.

Replacement of depleted antioxidants. The primary function of antioxidants is to help to eliminate harmful free radicals and oxidants. The intestinal mucosa contains an extensive system of antioxidants. Absolute levels of these antioxidants and the balance between the most important antioxidants are seriously impaired in intestinal mucosa during inflammatory bowel disease. Supplementation with antioxidants can improve symptoms of Crohn’s disease.

• Life Extension Booster, one softgel daily.

Replacement of depleted vitamins and minerals. Depletion occurs as a result of Crohn’s disease so it is vitally important to correct this disease-related malabsorption. Minerals often lacking in those suffering from Crohn’s disease include iron, magnesium, selenium, and zinc. Vitamins that are most lacking are the B-complex vitamins, folic acid, vitamin B6, and particularly, vitamin B12. Supplementation with these vitamins improves symptoms of Crohn’s disease by improving endothelial function.

• Life Extension Mix comes in pills, capsules or powder. Follow directions as listed on the label.

Calcium and magnesium are usually deficient in Crohn's disease. Supplements with extra minerals should be considered.

• Bone Restore, five tables daily

The amino acid glutamine is a major fuel and an important nitrogen source for the small intestinal cell. It maintains mucosal cell integrity and the gut barrier. L-glutamine supplementation might benefit conditions characterized by increased intestinal permeability such as food allergies. Glutamine is beneficial for the gastrointestinal tract.

• L-Glutamine Capsules, four to six 500-mg capsules daily.

Essential fatty acids found in cold water fish are beneficial. Fish oils have significant impact on inflammation generated during Crohn's disease. Life Extension has uncovered research and conducted clinical studies showing that addition of sesame lignans to fish oil enhances the oil’s beneficial effects. When fats are consumed they are metabolized into factors that either promote or suppress inflammatory reactions. Sesame lignans inhibit an enzyme (delta-5-desaturase) that converts dietary fat into arachidonic acid, a precursor to prostaglandin E2 and leukotriene B4.

• Super EPA/DHA with Sesame Lignans, two soft gels twice daily with meals.

Beneficial bacteria and when taken with fructose-oliogasaccharides (FOS) helps restore healthy bowel function and intestinal peristalsis

• NutraFlora, one teaspoon daily is suggested.

DHEA is a steroidal/prosteroidal hormone that inhibits TNF-alpha, a pro-inflammatory cytokine implicated in Crohn's disease. Blood testing can determine if you have a deficiency of this hormone. DHEA supplementation lowers pro-inflammatory cytokines and protects against their toxic effects; reducing inflammation and increasing absorption of nutrients. Healthy people take 15-50 mg of DHEA daily. Crohn's disease patients may take 100-200 mg per day of DHEA as long as they obtain proper hormone blood testing (refer to DHEA Replacement Protocol for specifics).

• DHEA, one to four capsules daily.

Soluble fiber maintains healthy bowel function and reduces the risk of colon cancer. Along with starches, glutamine, and fish oils; fiber may help control the malnutrition in Crohn's patients.

• PGX, up to 3 grams daily.

Additional iron may be taken if blood chemistry tests show a deficiency. A standard dosage is 15 mg of elemental iron daily.

• Iron Protein Plus, one capsule daily.

Butyric acid (also known as butyrate) is a short chain fatty acid produced when intestinal fiber is metabolized by healthy bacteria. Local administration of butyrate ameliorates inflammation in ulcerative colitis and Crohn’s disease. Butyrate enemas can relieve symptoms in ulcerative colitis. (Butyrate enemas may be purchased in drugstores.)

New pharmacological approaches are available for cases that do not respond to conventional and/or natural therapies; ask your doctor to consider administering the drug Leukine® (GM-CSF), starting with a low dose and working up to 4-8 mcg/kg/day for a period of eight weeks. Leukine® enhances neutrophil function and shows remarkable benefits in limited clinical studies.186 Refer to the Ulcerative Colitis protocol for additional information.

For more information contact the Crohn's and Colitis Foundation of America, (800) 343-3637.

Product Availability

Life Extension Booster, Life Extension Mix, Bone Restore, L-Glutamine, Super EPA/DHA with Sesame Lignans, NutraFlora, DHEA, PGX Fiber, and Iron Protein Plus can be obtained by calling 1-800-544-4440.

About the Authors

This protocol was written and edited by Corinna Underwood MA. Corinna has studied sociology of health and nutrition and has published articles in a broad range of health magazines in Canada, USA and UK. For several years she has been particularly interested in nutritional and complimentary therapies, particularly in relation to disease theories and cultural understanding of embodiment.

Sections were written and edited by Randall Lee Kohl, Ph.D., R.Ph., F.C.P., Senior Editor for LE Publications, Inc. Please direct only your comments to rkohl@lef.org. Direct questions to the Life Extension Health Advisory staff at (800) 544-4440.

CROHN'S DISEASE

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