Fish Oil for the Treatment of Crohn’s Disease

Heard about fish oil? This ill defined substance has gotten play in the popular health literature, but now there has been a study in Crohn’s disease published in the New England Journal of Medicine . The study showed that the preparation, Purepa, is effective. It should be available in a few years in the US.

There has been a fair amount of interest in fish oil as an antiinflammatory medicine over the years. In part this is driven by fish oil being “natural”. The scientific reason is that oils in the diet are the building blocks for certain chemicals the body makes, some of which are immune modulators. Fish oils contains a group of oils known as omega-3 fatty acids (chemically a double bond is present 3 down from the end of the carbon chain of the fat molecule). These oils are able to prevent the production of certain inflammatory molecules in the human body.

Fish oil per se is not a defined substance. There is the matter of variation of the fish, whether the oils is taken from whole fish sqeezings or just the fillets, and what processing is done. The whole fish issue is important because toxins (or perhaps useful drugs) are concentrated in fish livers. Processing is important because of stability. As with all supplements marketed as foods, the natural food pushers do not want regulation to be exerted upon them as it would add all sorts of complexities to their lives. As I see it, if they are going to push their own products, the consumer should be assured that the manufacturer can trace the source of raw material, have a regular way of making the stuff, keeps records of quality control, and does assays of the important ingredient(s). Additionally, the studies, if any, used to support the use of natural products often are used to recommend products different from those in the study. With something as unregulated, unassayed, and undefined as health food store products, who knows whether the health food store drug will do any good.

There were 39 patients in each group. P = 0.006 for the comparison of the two groups by log-rank analysis.

With this background, now comes a drug which is a fish oil preparation. Researchers in Italy used a fish oil preparation called Purepa, manufactured in Sweden, and coated the capsules with an enteric coating called Eudragit NE 30D. It is well defined and manufactured with the care a drug company takes. A study in the New England Journal of Medicine (NEJM 334(24):1557-1560, 13 June 1996) reported that patients with Crohn’s disease had less relapses when taking the medicine than did those taking placebo. The study was well done. It used a group of patients randomly assigned to either drug or placebo. Patients were not able to tell which drug they were on. (Which also implies that enteric coated Purepa does not have the nasty fish taste which can make fish oil hard to take.) The patients who were asked to participate were known to have a high chance of flares of the disease, based on their having all been in remission less than 2 years, with serum alpha 1-acid glycoprotein concentration > 130, alpha 2-globulin > 0.9, or a sed rate > 40. The findings were remarkable. The patients on drug had a relapse rate of only 41% compared to controls who had a relapse rate of 74% over the one year of followup. Diarrhea was a side effect in 4 of 39 fish oil treated patients vs 1 of 39 placebo patients. The diarrhea did not resolve when the drug was stopped in experimental or control subjects. The dosage of fish oil was 9×500 mg capsules per day, = 4.5 grams of fish oil per day. Interestingly, all relapses occurred within 7 months in both groups. Also, the fish oil group had improvement in all three serum measurements made, while the placebo group all had worsening of the measures.

The problems with the study concern whether the drug will be effective in all patients with Crohn’s, or only those patients like those in the study. This is a real issue – Crohn’s disease is a heterogeneous group, and the Italian group that published this may have selected a subset of Crohn’s that would respond differently. Also, this study was done in Italy. The Italian diet differs from a typical American diet, not to mention Scottish, New Zealand, Chinese, Dutch, Polish, German, French, or any cuisine that you may wish to identify. Italians also are heterogeneous in their diet, varying greatly from North to South, and inland vs seacoast. The study did not subgroup its results by region of Italy where subjects were born or lived, which would have been interesting.

It looks like this will be effective, however. Given the safety of the preparation it will be a welcome addition to treatment of Crohn’s. The variation in fish oil preparations available, along with the history of previous negative studies with fish oils, leads me to conclude that until a particular preparation is studied it will not be possible to say whether any particular fish oil preparation will work in Crohn’s. It is interesting that both placebo group and Fish Oil group had no more relapses after 7 months. It would be nice to know if the changes in any of the blood measures predicted who would relapse. The relapse curves also raise the question whether patients only need to be on the drug for 7 months to get the full benefit.

Stephen Holland, M.D.
University of Illinois College of Medicine at Urbana-Champaign

cA2 in Crohn’s disease

What is the “cure” for Crohn’s that has been reported in the news? There have been reports of an antibody that can treat Crohn’s disease. While not a cure, it may represent a new treatment that will more rapidly bring flares of Crohn’s under control.

[ The IBDPage has been around for a long time. Remicade (infliximab | Janssen) was the first anti-TNF drug available. Take this post as an interesting post from long ago – Ed.]

cA2 in Crohn’s disease

A fair amount of press has recently been seen about a new cure for Crohn’s disease. Unfortunately, this was very poor reporting. The drug that has garnered all this attention was called cA2, and now is named Infliximab. This drug is an antibody that binds an immune chemical called TNF-alpha. Antibodies are large proteins that can only be administered intravenously.The reports at the Digestive disease week meeting in San Francisco lastMay (May 1996) basically showed that in patients with severe Crohn’s disease,65% percent had an excellent response to administration of cA2. Patientswith Ulcerative colitis were not helped. Patients relapsed as the drugwore off. 

Thus, while not a cure, cA2 will probably be an important drug in the treatmentof Crohn’s disease. It will probably find its role in the treatment ofpatients with Crohn’s who are hospitalized for a severe flare. In thesepatients, the drug will probably allow faster control of the inflammation.The patients will still be treated with steroids, but the cA2 will allowfaster discharge. Interestingly, a lot of patients getting the drug at this time are patients who have been maintained as an outpatient who havebeen doing poorly with chronic fistulas or inflammation that has nevercome under control.

One aspect which has cause a lot of excitement in the scientific communityabout this drug is that it is one of the first success stories for immunologyresearch predicting clinical results. TNF-alpha is an early player in theimmune response, so blocking it should be effective. However, studies ofUlcerative Colitis patients showed that they do not have elevated levelsof TNF-alpha, while Crohn’s patients do. Thus, the effectiveness of cA2in Crohn’s but not in UC confirmed the immune studies in those patients.The research into what causes the lack of response in 35% of the Crohn’spatients will be interesting to follow.

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria

Salmonellosis Associated with a Thanksgiving Dinner

Many will enjoy eating turkey on Christmas. (Perhaps some on Hanukah – is turkey Kosher?) Some tips from the CDC on cooking can be found in this chilling report on a family that had a bacterial infection from Thanksgiving dinner.

The turkey can kill you.

The following is from the CDC’s MMWR publication. The MMWR can be downloaded from ftp://ftp.cdc.gov/pub/Publications/mmwr/wk/

Salmonellosis Associated with a Thanksgiving Dinner 

MMWR Morb Mortal Wkly Rep. 1996 Nov 22;45(46):1016-7.

On November 28, 1995, the county coroner’s office notified the ClarkCounty Health District in Las Vegas, Nevada, about a death suspected tohave resulted from a food-borne disease. This report summarizes the investigationof the outbreak of gastroen-teritis among persons who attended a Thanksgivingdinner. The investigation documented Salmonella serotype Enteritidis (SE)infection associated with eating improperly prepared turkey and stuffingcontaining eggs and emphasizes the need to use a meat thermometer to ensurecomplete cooking of turkey and stuffing. 

During November 25­-28, 1995, all six persons who attended a Thanksgivingdinner at a private home on November 23 and a seventh person who on November25 ate food remaining from the dinner had onset of abdominal cramps, vomiting,and diar-rhea. Two persons were hospitalized because of dehydration; athird person was found comatose at home and died from severe dehydrationand sepsis. Stool cultures obtained from three persons, including the decedent,yielded SE phage type 13a. Turkey and stuffing were the only foods eatenby all seven ill persons. No leftover food was available for culture. 

The Clark County Health District interviewed the ill persons (includingthe cook) to obtain details about the preparation and cooking of the turkeyand stuffing. On No-vember 22, a 13-pound frozen turkey was thawed for6 hours in a sink filled with cold water. After thawing, the packet ofgiblets (heart, liver, and gizzard) was removed, and the turkey was storedin a refrigerator overnight. However, on November 23, parts of the turkeywere noted to be frozen. The turkey was filled with a stuffing made frombread, the giblets, and three raw eggs, and then placed for 1 hour in anoven set at 350 F (177 C). The setting was lowered to 300 F (149 C) whilethe turkey cooked for an estimated additional 4 hours. The turkey was removedfrom the oven when the exte-rior had browned. A meat thermometer was notused. The stuffing was removed im-mediately and was served with the turkey.After the outbreak, health officials tested the oven set at 300 F (149C) and found the temperature to be 350 F (176 C). 

Reported by: O Ravenholt, MD, CA Schmutz, LC Empey, DJ Maxson, PL Klouse,AJ Bryant, Clark County Health District, Las Vegas; R Todd, DrPH, StateEpidemiologist, Nevada State Health Div. Foodborne and Diarrheal DiseasesBr, Div of Bacterial and Mycotic Diseases, National Center for InfectiousDiseases, CDC. 

Editorial Note: An estimated 2­4 million cases of salmonellosisoccur each year in the United States, resulting in at least 500 deaths( 1 ). Approximately 40,000 of these in-fections are culture-confirmed,serotyped, and reported to CDC through the National Salmonella SurveillanceSystem. In 1995, SE was the most common serotype reported, accounting for25% of the 40,720 serotyped culture-confirmed cases. Salmonellosis is frequentlyassociated with eating undercooked eggs and poultry. Undercooked eggs area particularly common source of SE infections. 

During 1988­ 1992, among foodborne disease outbreaks of salmonellosisreported to CDC in which a single food item was implicated, consumptionof turkey and eggs accounted for 4% and 14% of cases, respectively. Inaddition, eggs or foods containing eggs as a princi-pal ingredient caused64% of the SE outbreaks ( 2 ). Factors probably associated with the outbreakdescribed in this report included inadequate thawing, use of raw eggs inthe stuffing, and undercooking; in addition, the browned color of the turkeymay have caused the cook to believe that the turkey andstuffing were thoroughlycooked. Although the original source of the Salmonella is unknown, theraw eggs used in the stuffing probably contained SE, and these eggs probablywere incompletely cooked; undercooking may occur more commonly in tur-keysthat contain stuffing (J. Carpenter, Ph.D., University of Georgia, personalcommu-nication, 1996). 

Each year, an estimated 45 million turkeys are eaten in the United Statesat Thanks-giving (J. DeYoung, National Turkey Federation, personnel communication,1996). Salmonella infection may result from eating improperly cooked turkeyand stuffing ( 3,4). This risk for infection can be reduced by cookingstuffing outside the turkey. Guidelines prepared by the U.S. Departmentof Agriculture (USDA) for persons who choose to cook stuffing inside theturkey recommend preparing the stuffing immediately before it is placedinside the turkey, stuffing the turkey loosely, inserting a meat thermometerinto the center of the stuffing, and ensuring that the thermometer attainsa temperature of at least 165 F (74 C). Additional recommendations forsafely preparing and cooking a turkey include thawing the turkey completelybefore cooking, cooking in an oven set no lower than 325 F (163 C), andusing a meat thermometer to ensure that the innermost part of the thighattains a temperature of 180 F (82 C). Although the set temperatureand cooking time can be used as guides to determine whether food is completelycooked, inaccuracies in the actual temperature and incomplete thawing beforecooking can lead to undercooking. Use of a meat thermometer provides amore accurate determination of thorough cooking. Further advice on cookingturkeys and stuffing is available from USDAÕs Meat and Poultry Hotline,telephone (800) 535-4555. 

References 

1. Cohen ML, Tauxe RV. Drug-resistant Salmonella in the United States:an epidemiologic perspective. Science 1986;234:964­9. 

2. Bean NH, Goulding JS, Loa C, Angulo FJ. Surveillance for foodborne-diseaseoutbreaks United States, 1988­-1992. In: CDC surveillance summaries(October). MMWR 1996;45(no. SS-5). 

3. CDC. Foodborne nosocomial outbreak of Salmonella readingÑConnecticut.MMWR 1991;40: 804­6. 

4. CDC. Restaurant outbreak of salmonellosis due to undercooked turkey Washington. MMWR 1978;27:514,519.

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria