Crohn's disease is a long-term, chronic disorder of the intestine. The etiology (underlying cause) is unknown. In persons who have Crohn's disease, the gastrointestinal tract becomes inflamed and weak, making digestion difficult and leading to general physical debility. It is a relatively rare disease, occurring in approximately 1-5 people in every 10,000. Clustering of Crohn's disease has been shown in families. In the United States, the annual incidence of the disease is about two out of 100,000 persons, with a slight predominance among females. The incidence of Crohn's disease appears to be increasing in the Western world, leading one to suspect lifestyle factors as a promoter or cause. Crohn's disease is more common among Jews of middle European origin than among non-Jews, and it develops in twins and siblings at a much higher rate than would be predicted by chance.
The symptoms of Crohn's disease are similar to ulcerative colitis, and both conditions are categorized as inflammatory bowel diseases. To distinguish between them, your physician may need to examine a sample of intestinal tissue. As noted earlier, although the etiology of Crohn's disease is obscure, it is thought that certain antigens may activate immune cells in the intestinal wall. These immune cells then secrete proinflammatory agents (cytokines), such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1b (IL1b), that can further aggravate the inflammatory cascade. The result is thinning of the bowel wall (McDermott 1990). Since a large percentage of immune cells reside in the gastrointestinal tract, activation of these cells at this level is almost certain to cause gastrointestinal symptoms.
Crohn's disease can attack any part of the digestive system from the mouth to the anus, but it most commonly affects the ileum (lower portion of the small intestine) or the colon (large intestine). Ulcers form on the inner intestinal lining, and they eventually spread through the intestinal wall. As the affected part of the intestine becomes scarred and thick, the passage narrows, disrupting nutrient absorption and normal bowel function.Symptoms and Diagnosis
Crohn's disease is typically diagnosed among people in their 20s and 30s, but the disease also occurs in infants and children. More common in women than in men, Crohn's disease is rare in persons of Asian or African descent who live outside the United States. The disease is a lifelong ailment that can be controlled, but at present there is no cure or even a definitive cause. Crohn's disease patients usually experience excruciatingly painful attacks of abdominal pain and diarrhea followed by weeks, months, or even years of remission.
Development of abscesses or fistulas, or tubes that form a connection between two organs and allow the passage of fluid and stool, is a common complication of Crohn's disease. These connections can happen between the intestinal loops, the intestines, and the bladder or between the intestines and the skin. They often occur near the anus. Surgery may be required to close fistulas. Some Crohn's disease patients also have a tendency to manifest nonintestinal disorders, such as inflammation of the eyes; skin eruptions or rashes; kidney stones; or arthritis of the knees, ankles, and wrists. People who have had Crohn's disease for 10 years or more are at risk of developing colorectal cancer. Therefore, if you have Crohn's disease and are over age 30, you should have regular checkups, including screening for colorectal cancer.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. However, as with many other elements of the disease, it is difficult to make sweeping generalizations.)
- 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
- Arthritis flare-ups in the arms or legs with the above symptoms
- In young children, any of the symptoms above, plus failure to thrive; in older children, failure to grow at a normal rate
Although the actual cause of Crohn's disease is unknown, it may be an autoimmune disorder. Inflammation apparently occurs when the body's own immune system--for reasons not yet understood--attacks a part of the intestine.
In a published article in the June 2000 issue of Digestive Diseases and Sciences,
the authors suggest the possibility that various degrees of function and types of neutrophil impairment may manifest into specific genetic syndromes. This proposed theory differs from the current suggested course of the disease, in which genetic syndromes are believed to be responsible for progression of Crohn's into a disease state (Korzenik and Dieckorgraepe 2000). However, researchers and physicians concur that Crohn's disease is an immune response that causes inflammation. It is the suppression of inflammation that can decrease the injurious effects that the immune system inflicts on the Crohn's patient. However, according to the study researchers, it is those critical early events that may initiate Crohn's disease.
Furthermore, the researchers cite recent data that implicate bone marrow as playing a key role in the genesis of Crohn's disease and that 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. Interestingly, a diverse number of syndromes in which intestinal manifestations are almost indistinguishable from Crohn's disease all share a unifying feature. Each has a distinct deficiency in quantitative or qualitative neutrophil function, providing strong evidence that a functional neutrophil deficiency can result in a common intestinal phenotype of Crohn's disease (Korzenik and Dieckorgraepe 2000).
While the progression from neutrophil dysfunction to the generation of Crohn's disease is speculative, Korzenik and Dieckorgraepe conclude that a common pathway has been observed in neutrophil disorders associated with Crohn's disease. Neutrophils function as a first-time defense when microbes invade the mucosal lining of the intestine. Normally, neutrophils would mediate the rapid clearance of mucosal microbes. However, if the neutrophils are dysfunctional, monocytes-macrophages are recruited and activated, in turn triggering lymphocyte activation of the T cells. Neutrophils and macrophages produce pro-inflammatory cytokines, including tumor-necrosis factor alpha (TNF-a), which contributes to an immune response resulting in inflammation. The scientists point out that current therapy referred to as anti-tumor-necrosis factor therapy has been successful but does not address the underlying etiology of the disease.
The authors indicate that the impairment of neutrophil function may result from a combination of genetic and environmental influences. Smoking, NSAID use, and specific microbial flora are some of the environmental influences that can potentiate neutrophil dysfunction. While this report has promising implications, further research is required. The drug Leukine, which helps correct impaired neutrophil function, is described later.
There has been other research indicating the possibility of viral factors causing or contributing to Crohn's disease. Some scientists are exploring this theory. However, no specific viral agent has been identified.
Crohn's disease can usually be diagnosed by a variety of methods. In some cases, it is difficult to distinguish Crohn's disease from ulcerative colitis; therefore physicians may employ more than one diagnostic method. Common diagnostic tools include:
- X-rays of the large and small intestines
- Colonoscopy, usually including tissue biopsy
- Barium enema
Once Crohn's disease is diagnosed, routine blood tests for liver function and iron levels, as well as other blood tests, may be ordered, depending on the treatment being considered, to ensure that other existing health conditions do not interfere with the healing process.
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 manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.
- Moderate-severe disease applies to patients who have failed to respond to treatment for mild-moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.
Severe-fulminant disease applies to patients with persisting symptoms despite the introduction of outpatient steroids or individuals who present with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.
- Remission refers to patients who are asymptomatic or without inflammatory sequelae and includes patients who have responded to acute medical intervention or have undergone surgical resection without gross evidence of residual disease. Patients requiring steroids to maintain their well-being are considered to be "steroid-dependent" and are usually not considered to be "in remission" (Hanauer et al. 2001).
- Pro-Inflammatory TNF-a
- Granulocyte-Macrophage Colony-Stimulating Factor
- Total Parenteral Nutrition
- Growth Hormone Research
As noted earlier, Crohn's disease is not curable at this time. Depending on severity of the symptoms, medical treatment typically involves a three-pronged approach to controlling the disease: First, drug therapy and a restricted diet are explored; then if necessary, hospital treatment is initiated; the last resort is surgery.
Because there is no cure for Crohn's disease, patients and their physicians try to take steps to avoid recurring attacks for as long as possible. In cases of active disease, if that is not possible, achieving remission is pursued as quickly as possible. Some patients remain on maintenance medications even when there are no symptoms present. Children with Crohn's disease may require high-protein, high-calorie liquid supplements to keep their growth on track because the disease is particularly devastating in children.
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 many years without interruption and are given in varying dosages depending on the severity of the symptoms.
Aminosalicylates are given orally or as a rectal suppository. They interrupt colonic inflammation. Without inflammation, the symptoms of diarrhea, bleeding, and abdominal pain are greatly diminished. However, many people find that they are allergic to aminosalicylates, which is sometimes manifested by vomiting and headaches or with even more severe symptoms. When a patient starts taking aminosalicylates, if new symptoms occur, particularly of this type, it is important to contact the prescribing physician immediately and advise him of all symptoms.
In cases of active Crohn's disease, steroids such as prednisone are commonly prescribed alone or with aminosalicylates to reduce inflammation of the intestines. Use of steroids can be problematic because of the potential for difficulties associated with the severe side effects of steroids. Side effects of steroids can include:
- Cushing's syndrome
- Muscle disorders
- Hair loss
- Weight gain
- Suppressed immune system and the accompanying risks
- Hormone imbalance
Even with the associated risks, steroids such as prednisone are often used during the acute stage to help get the symptoms under control. Prednisone mimics the effects of the body's natural corticosteroid hormones by suppressing the release of inflammatory cytokines. Once under control, aminosalicylates are taken for maintenance therapy. Tapering off the use of steroids represents a critical time during disease treatment. Many patients find themselves precariously trying to remain in remission while also weaning themselves from steroids.
To reduce the need for steroids, immunosuppressants such as azathioprine, 6-mercaptopurine (also used in the treatment of some cancers), or cyclosporine may be substituted. Various chemotherapy agents and organ transplant antirejection drugs are also used. Again, these medications have their own problematic or dangerous side effects. Therefore, thoughtful consideration of a treatment plan coordinated by the patient's physician is required. All aspects of the treatment plan must be effectively communicated to the patient. Antidiarrheal agents may be taken for mild bouts of diarrhea, as well as antispasmodics for cramping. When patients have arthritis-like symptoms, antiarthritis medications may also be taken. In cases of severe disease, patients often require a bland, well-balanced diet.Reducing Levels of Pro-Inflammatory TNF-a
First introduced in 1995, a new treatment with a monoclonal antibody known as Infliximab (Enbrel) was used with success when other conventional treatments had failed (van Dullemen et al. 1995; Mortimore et al. 2001). Infliximab functions by reducing intestinal inflammation caused by TNF-alpha and destroying TNF-alpha producing cells. This treatment has been extremely effective in patients who have been resistant to other forms of treatment, even steroids. It can create remission in up to 80% of those in whom it is used. Improvement at 4 weeks was observed in more than 80% of patients treated with 5 mg/kg, and more than 50% achieved a clinical remission (Feagan et al. 2001). Fistulas also healed quickly. After treatment with Infliximab, compared to baseline, patients with Crohn's disease have decreased levels of serum IL-6 (an inflammatory immune factor) and C-reactive protein (Agnholt et al. 2001). Elevated concentrations of TNF-alpha have been found in the stools of Crohn's disease patients, correlating with elevated disease activity. Treatment with Infliximab reduces infiltration of inflammatory cells and the production of TNF-alpha in inflamed areas of the intestine.
Retreatment with Infliximab is likely to be necessary on an ongoing basis to prevent relapse. The long-term side effects are unknown. In addition, initially there can be severe side effects, including transfusion-type reactions, because Infliximab is an antibody that is being introduced into the patient intravenously. Infliximab infusions have been associated with both acute and delayed infusion reactions, including 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 presumed requirement for repeated infusions over time (Lugering et al. 2001; Martorana et al. 2001; Miller et al. 2001; Mortimore et al. 2001; Sandborn et al. 2001; Hove et al. 2002).Granulocyte-Macrophage Colony-Stimulating Factor
As stated previously, treatment for Crohn's disease is aimed at immunosuppression. Yet, as Dieckgraefe and Korzenik point out in Lancet (2002), inherited disorders associated with defective innate immunity often lead to the development of Crohn's-like disease. Based upon this theory, the researchers performed an open-label dose-escalation trial (4-8 mcg/kg/day) to investigate the safety and possible benefit of granulocyte-macrophage colony-stimulating factor (GM-CSF) on 15 patients with moderate to severe Crohn's disease (Dieckgraefe and Korzenik 2002).
The results were promising. None of the patients was found to have any worsening of the disease while under treatment, and adverse events were negligible. Further, the researchers reported that patients had a significant decrease in mean Crohn's disease activity index (CDAI) score during treatment. After 8 weeks of treatment, mean CDAI had fallen by 190 points, and overall 12 patients had a decrease in CDAI of more than 100 points, while 8 patients achieved clinical remission. Retreatment was effective, and overall the treatment was associated with increased quality-of-life measures (Dieckgraefe and Korzenik 2002).
While GM-CSF may offer an alternative to the traditional immunosuppression treatment of Crohn's disease, it is important to note that the authors conclude that their findings warrant further validation. They cite the small study size, the very subjective self-report format, and the fact that it was an uncontrolled study as the reasons for ongoing follow-up studies to be performed. GM-CSF is sold under the trade name Leukine and is typically used to restore immune function in cancer patients who have undergone bone marrow-depleting chemotherapy.Total Parenteral Nutrition
If a patient becomes severely ill and has diarrhea and weight loss, intravenous (IV) nutrition administered in a hospital setting can allow the intestines to have a "resting" period. Total parenteral nutrition (TPN) is also used to rest the intestinal tract. Usually TPN nutrition is administered via a tube directly into the bloodstream by an infusion system. After stabilization, some patients may require continuation of IV nutrition at home with the aid of a visiting nurse service.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 from the mouth to the anus, surgery is directed at removing only the severely inflamed part of the intestine. The goal of surgery is to preserve as much of the intestine as possible. 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 severe and less debilitating than they were previously. However, when the disease does recur, it usually does so at the site of the last surgery.Growth Hormone Research
A study published in the New England Journal of Medicine suggested that administering growth hormone (GH) to patients with Crohn's disease may help to resolve many of their associated symptoms (Slonim et al. 2000). In a 4-month study, 19 adults with moderate to severe Crohn's disease were put on a regimen of daily self-injections of GH (5 mg a day for the first week, then 1.5 mg a day). Headaches and edema were reported by 10 and 5 patients, respectively; however, these symptoms dissipated within 2-3 weeks. Marked improvement in symptoms within the first month of self-administered treatment with increasing benefits over the next 3 months was seen. Specifically, the GH group showed significant improvement in three areas of disease activity by the end of the study, which included the number of liquid or very soft stools a day, severity of abdominal pain, and increased feeling of well-being. In addition, half of the patients in the GH group who were on other medications were able to reduce their dosages. The researchers also noted that supplemental protein intake was further enhanced in the intestinal tract when growth hormone was administered (Slonim et al. 2000).NUTRITION, DIET, AND VITAMIN SUPPLEMENTATION
Because most medications for Crohn's disease have an abundance of side effects, many patients understandably focus on nutrition and diet as a means of staving off active disease or helping to induce remission. There is substantial evidence that intolerance to certain foods and other nutritional factors play a large role in the practical management of Crohn's disease through nutritional modification. Early studies have shown that Crohn's patients tend to consume high amounts of simple sugars, either at the time of diagnosis or following it (Mayberry et al. 1981; Jarnerot et al. 1983; Persson et al. 1992). The propensity to consume simple carbohydrates, which often continues in the main phase of the disease, indicates that many Crohn's patients have not been counseled correctly to reduce their consumption of refined carbohydrates (Kruis et al. 1987).
Indeed, early research also suggested that consumption of highly refined foods may be involved in the etiology itself (Grimes 1976). In another early study, 80% of patients who were on a low carbohydrate diet that excluded all refined sugar had significant symptom relief within 18 months, whereas 40% of patients on a high carbohydrate diet that was high in refined sugar had to discontinue the diet because of flare-ups (Brandes et al. 1981).
Nutritional management of Crohn's disease has the potential for a larger, more beneficial role than methods that primarily use anti-inflammatories and steroids as a first line of treatment. As early as 1990, there were studies reporting that the use of an elemental diet can induce a remission equal to, if not better than, prednisone (Giaffer et al. 1990; O'Keefe 1996). An elemental diet contains the essential elements of good nutrition, usually in a liquid form and usually with hypoallergenic protein contents. In patients who were already taking prednisone, the drug could be reduced or eliminated in 50% or more of patients who followed an elemental diet (Verma et al. 2001). In addition, while on an elemental diet, inflammatory parameters and intestinal permeability tended to decrease (Teahon et al. 1991).
Because many Crohn's patients are often nutritionally deprived at diagnosis, using nutrition to induce remission in confirmed Crohn's disease provides an opportunity for the patient to become nutritionally replete, possibly for the first time in many years. Unfortunately, the elemental diets used by conventional practitioners are often unpalatable. However, detoxification programs do exist in the armamentarium of nutritional physicians that are quite palatable and can introduce concentrated vitamins and minerals needed by the patient for recovery. Nutritional biochemist and researcher Dr. Jeffery Bland has popularized the notion of the 4-R program for managing intestinal disorders of this nature. The R's stand for (1) remove, (2) replace, (3) reinoculate, and (4) repair (Liska et al. 2001).
The protocol would proceed as follows:
Remove all suspicious foods from the patient's diet that precipitate inflammation. The following have been found to be the most likely to be troublesome: dairy, eggs, nuts, fruit, tomatoes, corn, wheat or gluten, and red meat. All refined carbohydrates should be removed. Also, all fats except for essential fatty acids should be eliminated because hard or trans fats, in particular, have been found to be detrimental for persons with Crohn's disease (Heckers et al. 1988; Lorenz-Meyer et al. 1996). Products such as Vivonex, UltraMaintain, or UltraClear can be used at the outset. UltraClear is preferable because it contains sufficient fiber to maintain regular evacuation of the bowel. Additionally, removal of gastrointestinal parasites, undesirable bacteria, or fungal elements that may be present and contribute to symptoms is important. Removal of yeast overgrowth by using an antifungal drug (e.g., oral nystatin) may also be required.
By the time Crohn's disease is diagnosed, most patients are already in nutritional imbalance. Replacement of vital nutrients may consist of a good multivitamin and mineral complex, together with minerals that have been found to be lacking. Minerals often lacking are iron, magnesium, selenium, and zinc. Vitamins found to be most lacking are the B-complex vitamins, including folic acid, vitamin B6, and particularly vitamin B12, which is absorbed from the end portion of the small intestine. A German study in 1998 examined deficiencies of vitamins and trace elements in patients with inflammatory bowel disease. The records from 392 outpatients, 279 with Crohn's disease and 113 with ulcerative colitis, were analyzed. Deficiencies were found in 85% of patients with Crohn's disease, predominantly deficiencies of iron and calcium. Less frequently, deficiencies of zinc, protein, cyanocobalamin (B12), and folic acid were found (Rath et al. 1998).Note:
Long-term use of steroids warrants the inclusion of supplemental calcium and vitamin D to prevent the risk of osteoporosis (Hoffmann 2002). Patients with Crohn's disease usually have a moderate anemia that is often caused by several factors: iron deficiency; vitamin B12 deficiency related to extensive disease of the terminal ileum; folate deficiency produced by anorexia and the consequent poor intake of dietary folic acid; or by inhibition of folate absorption by sulfasalazine, one of the common drugs used to reduce inflammation. Other nutritional factors may need to be added at a later time. See Repair.
A normal healthy intestine contains about 5-7 lbs of "friendly bacteria" that are responsible for manufacturing some vitamins and gut cell food. In a diseased intestine, these bacteria are out of balance and are often absent, having been replaced by pathogenic organisms, including yeast overgrowth. Reinoculation consists of taking mixtures of Lactobacillus acidophilus and Lactobacillus bulgaricus with fructose oligosaccharides (FOS). L. bulgaricus is found in Jerusalem artichoke and other vegetables. It is a substrate or food for the Lactobacillus species. Stool samples provide clinicians with information regarding these overgrowth factors, pH of the stool, and the balance of fatty acids required for health.
Frequently in Crohn's disease it is found that the lining of the small intestine has become permeable. The once-protective layer now permits antigens and other incomplete digestive products to pass through the bowel wall. Repair of the protective layer consists of adding nutrients such as glutamine, pantothenic acid (vitamin B5), zinc, 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 rest of the body through the gastrointestinal lymphoid-associated tissue (GALT), where it increases release of proinflammatory mediators.
At least one study reported that patients who did not have restoration of their small bowel mucosal integrity at discharge from the hospital (i.e., those who still had a "leaky gut" when they left the hospital) had a very high probability of relapse (76-81%) within 1 year. Crohn's disease patients with normal gut mucosal integrity and healing of the gut at release from the hospital had a less than 5% probability of relapse within 1 year. Relapse rate depended greatly on the patients' GI mucosal integrity (evaluated by lactulose/mannitol challenge) on discharge (Wyatt et al. 1993).SPECIFIC NUTRITIONAL COMPONENTS
- Butyrate and Glutamine
Significant research has focused on specific nutrients such as essential fats and antioxidants. Humans evolved by consuming a diet that contained about equal amounts of n-3 and n-6 (also known as omega-3 and omega-6) essential fatty acids ( named by referring to the carbon double bond position ). Omega-3 fatty acids are found in nuts (especially walnuts), seeds, and fish oil, whereas omega-6 is generally found in animal fats such as beef and poultry, as well as in some processed oils (e.g., corn, sunflower seed, safflower seed, cottonseed, and soybean).
Over the past 100-150 years, there has been an enormous increase in the consumption of n-6 fatty acids as a result of the increased intake of vegetable oils. In Western diets today, the ratio of n-6 to n-3 fatty acids ranges from approximately 20:1 to 30:1 instead of the traditional range of 1:1 to 2:1. It is thought that a high intake of n-6 fatty acids shifts the physiologic state to one that is primarily inflammatory by producing inflammatory hormone-like molecules known as prostaglandin E2 series. However, the downstream products of n-3 fatty acids, known as prostaglandin E1 and E3 series, have anti-inflammatory properties. The beneficial effects of n-3 fatty acids have been shown to have an additional benefit in the secondary prevention of coronary heart disease, hypertension, Type-II diabetes, and ulcerative colitis and Crohn's disease in some patients (Simopoulos 1999).
In an article entitled "Modulation of Intestinal Immune System by Dietary Fat Intake: Relevance to Crohn's Disease," Miura and colleagues stated: "Both the amount and type of dietary fat modulate intestinal immune function" (Miura et al. 1998). Studies have focused on the essential fats found in fish oils. These fats are known as EPA and DHA and are found in the fat of cold water fish. They have significant impact on inflammation generated as a result of Crohn's disease. However, balance is essential. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system in animals fed an elemental diet. (Note: Dietary oleic acid is a C-18 fatty acid that is found in certain oils such as 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.
We know that the fatty acid profile in patients with Crohn's disease is significantly associated with disease activity and serum antioxidant concentrations. This observation, along with diminished antioxidant defense in patients with both active and inactive Crohn's disease, indicates that antioxidants should be considered in the therapy.
In one randomized, double-blind, placebo-controlled study, 25 Crohn's disease patients received either placebo, antioxidants, or n-3 fatty acids plus antioxidants for 3 months, in addition to their regular diet. Antioxidant status was assessed by blood biochemical parameters. Serum concentrations of the antioxidants selenium, vitamin C, and vitamin E and the activity of superoxide dismutase and total antioxidant status were significantly increased after antioxidant supplementation. Furthermore, compared with controls, serum concentrations of beta-carotene, selenium, and vitamin C and the activity of glutathione peroxidase (GPx) were significantly lower before supplementation; however, after antioxidant supplementation, these levels were not significantly different from controls (except for GPx). In the n-3 fatty acids plus antioxidants group, supplementation significantly decreased the proportion of arachidonic acid ( an n-6 essential fatty acid and proinflammatory ) and increased the proportion of EPA and DHA (omega-3 fatty acids).
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