Digestive Health Newsletter

What Causes Inflammatory Bowel Disease?

Daniel H. Present, MD

Volume 2, 
June 01, 2004

by Daniel H. Present, MD

Daniel H. Present Daniel H. Present, M.D. is Clinical Professor of Medicine at the Mount Sinai School of Medicine and an attending physician at the Mount Sinai Hospital. He is an internationally recognized expert on inflammatory bowel disease, and especially Crohn’s disease. Dr. Present has published over 120 articles on inflammatory bowel disease. In addition to his many publications, Dr. Present has served on the editorial boards of major medical journals and has written and produced numerous videotapes for physician and patient education on ulcerative colitis and Crohn’s disease. He has been honored many times by his peers and students for his leadership and teaching.



Table of Contents

Introduction

Etiology is the term used in medicine to describe the cause or reason for the development of a disease or condition. My patients who are newly diagnosed with either ulcerative colitis (UC) or Crohn’s disease (CD) are often concerned about how they developed these diseases and what it means to their future and their families. They want to know what causes it, and if there is anything they did to provoke the illness. They would like to know if there is anything they can do to prevent anyone else in the family from developing the same problems.

It is very important to note at the start of this newsletter that we do not know what truly causes UC or CD (known together as Inflammatory Bowel Disease or IBD). It is also important that you realize you are not to blame for your disease. However, there are steps you can take to treat your symptoms and multiple medications available today for IBD. For more information on what you can do as a patient to control your symptoms, please refer to the newsletter by Dr. Hanauer, "Staying on Medication – Your Health Depends On It," which is available by clicking on the link on the right side of this page.

In this newsletter, I will address some of the factors that could possibly be attributed to developing IBD. I will also answer some of the most common questions I receive from my patients regarding the cause of IBD and if there is anything they can do to prevent others close to them from getting it.

What Causes IBD?

As I stated above, at this time we do not fully understand what causes UC and CD. We do know that these are complex conditions, which are influenced by genetic, environmental, and immune system factors. However, at this time we do not know how much importance to attribute to each of these factors.

We do know that genetic factors play a major role in determining who is susceptible to IBD. It clusters in families and, in fact, the presence of a positive family history outweighs all other known risk factors for the future development of IBD.

Genetic Factors

Studies of first-degree relatives (parents, children, and siblings) and of twins have taught us that if one member of the family has UC, the risk that another first-degree relative has or will develop the disease is 8-15 times more likely than that of an unrelated person. The increased risk for CD is 20-35 times more likely among first-degree relatives than among unrelated persons. The genetic linkage for CD is greater than that for UC and much greater than that for other common genetically linked diseases, such as type 1 diabetes or hypertension.

Some ethnic groups are at increased risk for IBD as well, which also points to a genetic role in development of these illnesses. Jewish people of European descent (often called Ashkenazi Jews) are 2-9 times more likely to contract IBD compared with their non-Jewish neighbors irrespective of diet or religious observances. Caucasians and African Americans are more likely to have IBD than Hispanics or Asians, although recently CD has become more common in the Japanese. Another fact pointing to a genetic role is that individuals who have certain other diseases that tend to run in families, such as psoriasis, also develop IBD more frequently.

Complex mutations, or alterations, of several genes appear to contribute to the development of IBD. For example, patients who have two mutations, which is the minimum number commonly thought necessary to develop CD, still may not develop CD because an environmental trigger is absent. It is not a simple genetic factor like the development of blue eyes or brown eyes. Nonspecific genes are believed to increase the risk for inflammation that characterizes IBD in general, while others relate more specifically to either UC or CD.

As you should be aware, IBD is a complex disorder in which multiple genes place people at increased risk for developing the disease. Additional information about IBD and genetics is available on the Internet at www.ibd.patientcommunity.com and other Web sites.

Environmental Factors

Our understanding of the relationship between genetics and IBD is far from complete. While our understanding of environmental factors is also incomplete, some specific risk factors that predispose patients to developing IBD are known. An example is cigarette smoking, which is a significant risk factor for CD but not for UC. CD patients who smoke have a more severe disease course and a more rapid recurrence rate after surgical intervention.

Conversely, cigarette smoking may be somewhat protective against the development of UC, and stopping smoking may trigger the onset of the disease. The nicotine in tobacco may be the major factor, but using the nicotine patch in UC patients provides only minimal relief. Because tobacco, in any form, places people at a high risk for other serious, life-threatening diseases I do not routinely recommend it to my patients as a strategy for controlling IBD.

Bacteria and viruses have also been implicated in the development of IBD. The intestine normally contains large numbers of both "good and bad bacteria." Healthy people typically experience no health consequences from these bacteria. However, in people with IBD, common types of bacteria may actually cause harm to the wall of their intestines and trigger the inflammation in IBD.

Use of nonsteroidal anti-inflammatory drugs (NSAIDS), such as the various brands of ibuprofen and naproxen, may be a major factor in triggering IBD. While not all studies have implicated NSAIDS, in one recent study nearly a third of patients experienced either a relapse or the onset of their illness shortly after taking NSAIDS. I ask all of my IBD patients to contact me prior to using these medicines to see if they are truly required; you should discuss them with your doctor as well. More information about the role of NSAIDS and infectious agents and IBD can be found at www.ibd.patientcommunity.com and www.medicinenet.com.

IBD is more common among people living in developed countries than those living in less developed countries and in people living in urban rather than rural areas. It is also somewhat more common among individuals with a higher socioeconomic status. The incidence of IBD increases among people who emigrate from low-risk geographic areas to high-risk geographic areas. Such observations provide further evidence that environmental factors play an important role in the development of IBD. One theory is that children in underdeveloped countries may be exposed to infections that are not common in developed countries. This exposure may lead to a more resistant immune system that prevents the subsequent development of IBD.

Because environment is a factor, there has been speculation about the role of diet in the development of IBD. At the present time, research has not demonstrated a major role for diet. Nonetheless, much is made of diet, especially through the Internet and news media. Little evidence exists to support these claims. You can discuss dietary options with your physician and also visit www.ccfa.org/research/info/diet.

Immune System Factors

The two major factors, namely genetics and environment, are now linked to a third factor: patients with IBD have a disturbance in their normal mucosal immune function. For example, it’s the role of the body’s immune system to respond to microorganisms in the diet. Our normal immune system will react when it is threatened by a harmful bacteria or virus. In patients with IBD, however, the immune system tends to overrespond to these threatening agents and, rather than quieting down after the threat has subsided, it continues to overreact, which results in continued inflammation.

Now I’ll answer some of the specific questions that my patients ask regarding etiology.

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Frequently Asked Questions

How did I get this disease?

Currently the cause of IBD is believed to be a complex combination of genetic susceptibility and environmental triggers that result in an overreactive immune response. We really cannot be sure at this time how an individual acquires IBD, and it is probably not the same cause for each patient. The most important thing that I can tell you is that you are not to blame.

While stress can aggravate IBD, you did not develop UC or CD because you worry too much, work too hard, or eat the wrong foods. However, if you have CD and you are a smoker, I suggest you try to quit immediately. Additionally, when you develop this illness you must continue to take your medicines as prescribed by your physician. As I mentioned earlier, Dr. Hanauer’s newsletter stressed the importance of maintaining health through proper use of medication. Even though you did nothing wrong to develop IBD, you must commit yourself to your own wellness to keep it under control.

Is IBD contagious?

The answer is simply, "No. IBD is not contagious." These diseases do not spread through human contact. Developing IBD is a complex combination of genetic, environmental, and immune system factors.

If genetics plays a role, what are the chances that I am going to pass this disease to my children?

Specific genes associated with IBD vulnerability have recently been identified on several chromosomes. We know more about some of these genes than others. No defined mode of inheritance has been found, but we think that two or more susceptible genes are required for an inherited risk for IBD to occur. Among Caucasians, we estimate the risk to children of one affected parent to be 5-10%. The risk to children of two affected parents is over one-third and may be as high as 50%. The risk is higher when there is a strong family history of IBD, when IBD has occurred at an early age, and when the family is of Jewish descent. Unfortunately, insufficient data is available to accurately calculate the risk in non-Caucasian families.

Can I do something to prevent other members of my family from getting IBD?

We do not have strong recommendations for preventing IBD because we do not know exactly what causes it, but several actions may be helpful.

We feel that smoking is bad for everyone. If you have CD, avoid tobacco smoke. Both tobacco smoking and possibly exposure to second-hand smoke may increase your family’s risk.

Theoretically, if you have a strong family history of IBD it might be helpful to limit your family’s use of NSAIDS. While these have not been shown to cause IBD, they have been associated with damage to the wall of the intestines as well as with relapses in patients who already have IBD. Your doctor should be consulted on the advisability of using NSAIDS for any specific illness. Do not use them indiscriminately.

Should I, or other members of my family, have genetic testing?

At this point, I do not recommend genetic testing for most people. Screening of unaffected individuals is not very helpful because genetic tests at this time cannot accurately predict or rule out the possibility of developing disease.

The likelihood of a positive genetic predisposition varies widely and is affected by race, ethnicity, and environment, as well as the number of people in the family affected by the disease. At this time genetic testing is considered a research tool and is not used routinely. However, I hope this recommendation will change in the future as more specific genetic information is discovered.

I have heard that people born between September and February are more likely to have IBD. Is this true?

Population-based studies have suggested a higher prevalence of IBD among people born in certain months; however, many of these studies contained errors that when corrected have failed to demonstrate a significant relationship between birth month and IBD. Seasonal patterns and relapse of IBD may occur for some people. Unfortunately, it is difficult to reach final conclusions from this information because the number of patients studied is small and the seasons in which relapse is most frequent vary from country to country. However, the presence of seasonal variation does support the view that environmental factors play a significant role in IBD.

Does having IBD increase my risk for any other diseases?

Unfortunately, yes. But the good news is that many of these diseases are treatable. One of the most common problems is anemia, a deficiency in red blood cells that affects about half of all IBD sufferers. This may require treatment with iron, folic acid, or vitamin B12.

Individuals with IBD have an increased risk of developing several types of arthritis. One form affects the spine but does not usually cause deformities. Another type affects knees, wrists, elbows, and ankles. Fortunately, this type of arthritis is self-limited and disappears with treatment of the IBD.

IBD is associated with skin disorders, such as psoriasis, erythema nodosum (painful bumps on the skin) and pyoderma (ulceration of the skin). A small percentage of patients will develop eye inflammation. These are all treatable conditions that should be discussed with your physician.

People with IBD experience a somewhat increased incidence of thrombosis (blood clots) as well as an increased incidence of kidney stones and gallstones. A significant illness called sclerosing cholangitis, in which the liver ducts become narrowed, occurs in a small percentage of patients. The most serious illness for which IBD sufferers have an increased risk is colorectal cancer. Subsequent issues of this newsletter will cover risk from other diseases and complications of IBD in greater detail.

What about cancer?

IBD patients do have an increased risk for colorectal cancer. The greatest risk is in those patients who have the most extensive forms of colitis and who have had the disease for the longest duration. The risk is also increased in patients with a family history of colon cancer and in those with sclerosing cholangitis.

The overall prevalence of colorectal cancer in patients with IBD is approximately 4%, but risk increases over time with a 2% incidence of cancer after 10 years, a 9% incidence after 20 years, and a 19% incidence after 30 years of disease.

However, the good news is that colorectal cancer is one of the most preventable and treatable cancers through lifestyle changes and early detection. Exercising regularly and eating healthfully to maintain normal weight, avoiding tobacco, and staying on your medication are important things you can do to prevent colorectal cancer. The other major thing you can do is to have regular colorectal cancer screening as recommended by your doctor. This usually entails a colonoscopy.

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Summary

In summary, the development of IBD is related to genetic and environmental factors with a subsequent overreactive immune system. But with our current state of knowledge it is not possible to say exactly how much each element contributes to disease vulnerability or to predict who will get IBD.

Remember, you are not to blame for your disease and the disease is not contagious. Relationships between IBD and food, stress, seasonal variation, and infectious agents have not been established. More research is needed to verify, or rule out, the many environmental factors that have been proposed as potential culprits.

Despite this uncertainty, we have come a long way in increasing our knowledge of the causes and treatments for IBD. There are multiple effective treatments available today for both UC and CD so please discuss these with your physician and take these medications as they are prescribed for you. The approximately one million people living with IBD in America today have better care and prospects for longer, more satisfying lives than ever before.

The next newsletter, Volume 3, "The Clinical Course of IBD" will discuss how IBD affects patients over time including its effects on parts of the body other than the intestines, as well as common complications and how you can help to control them.

CCFAThis information has been reviewed and approved by CCFA's National Scientific Advisory Committee.

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Important Safety Information about AZASAN

WARNING: Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS section in complete Prescribing Information.

AZASAN® (azathioprine tablets) 75/100 mg is indicated as an adjunct for the prevention of rejection in renal homotransplantations, and also for the management of active rheumatoid arthritis to reduce signs and symptoms.The most commonly reported side effects associated with AZASAN therapy are leukopenia and/or thrombocytopenia, secondary infections, neoplasia, nausea, vomiting, diarrhea, fever, myalgias, skin rashes, and hepatotoxicity. AZASAN therapy should be given cautiously when used concomitantly with allopurinol, ACE inhibitors, and other agents affecting myelopoiesis. AZASAN is contraindicated in pregnant and lactating women and in patients who have shown hypersensitivity to this product.

Consult with your physician to see if this product is right for you.

Complete Prescribing Information for AZASAN, including BOXED WARNINGpdf

Important Safety Information about METOZOLV® ODT

WARNING: TARDIVE DYSKINESIA

See full prescribing information for complete boxed warning.

Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. The risk of developing tardive dyskinesia increases with the duration of treatment and the total cumulative dose.

Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.

Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia.

METOZOLV® ODT (metoclopramide HCl) is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux disease (GERD) who fail to respond to conventional therapy and for the relief of symptoms associated with acute and recurrent diabetic gastroparesis (diabetic gastric stasis) in adults. Therapy should not exceed 12 weeks in duration. Take on an empty stomach up to four times daily, at least 30 minutes before eating and at bedtime.

METOZOLV ODT is contraindicated in patients with intestinal obstruction, hemorrhage, or perforation; pheochromocytoma; known sensitivity or intolerance to metoclopramide; epilepsy; or are receiving concomitant medications with extrapyramidal reactions.

Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, occur in approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years of age and are even more frequent at higher doses.

Drug-induced Parkinsonism can occur during metoclopramide therapy, more commonly within the first 6 months after beginning treatment, but also after longer periods. Patients with a history of Parkinson’s disease should be given metoclopramide cautiously, if at all, since such patients can experience exacerbation of Parkinsonian symptoms when taking metoclopramide.

There have been rare reports of an uncommon but potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated with metoclopramide. Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered consciousness, and evidence of autonomic instability. The management of NMS should include immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy.

Depression associated with metoclopramide use has occurred in patients with and without a history of depression. For those patients with a prior history of depression, metoclopramide should only be given if the expected benefits outweigh the potential risks.

In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, caution should be exercised when metoclopramide is used in patients with hypertension. Any rapid rise in blood pressure associated with METOZOLV ODT use should result in immediate cessation of metoclopramide use in those patients.

Since metoclopramide produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. If these side effects occur at any time in any patients during metoclopramide therapy, the drug should be discontinued.

Adverse reactions, especially those involving the nervous system, may occur after stopping the use of METOZOLV ODT.

In clinical studies, the most frequently reported adverse events (≥2% occurrence) were headache, nausea, fatigue, somnolence, and vomiting.

Complete Prescribing Information for METOZOLV ODT, including BOXED WARNING pdf

Important Safety Information about OSMOPREP

WARNINGS

There have been rare, but serious reports of acute phosphate nephropathy in patients who received oral sodium phosphate products for colon cleansing prior to colonoscopy. Some cases have resulted in permanent impairment of renal function and some patients required long–term dialysis. While some cases have occurred in patients without identifiable risk factors, patients at increased risk of acute phosphate nephropathy may include those with increased age, hypovolemia, increased bowel transit time (such as bowel obstruction), active colitis, or baseline kidney disease, and those using medicines that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and possibly nonsteroidal anti–inflammatory drugs [NSAIDs]).

It is important to use the dose and dosing regimen as recommended (PM/AM split dose).

OSMOPREP® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets are indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. Considerable caution should be advised before OSMOPREP is used in patients with severe renal insufficiency, congestive heart failure, ascites, unstable angina, gastric retention, ileus, severe chronic constipation, bowel perforation, toxic megacolon, gastric bypass or stapling surgery, or hypomotility syndrome. Use with caution in patients with impaired renal function, patients with a history of seizures or at higher risk of seizure, patients with higher risk of cardiac arrhythmias, known or suspected electrolyte disturbances (such as dehydration), or people taking drugs that affect electrolyte levels. Patients with electrolyte abnormalities such as hypernatremia, hyperphosphatemia, hypokalemia, or hypocalcemia should have their electrolytes corrected before treatment with OSMOPREP.

OSMOPREP is contraindicated in patients with a known allergy or hypersensitivity to sodium phosphate salts or any of its ingredients, and in patients with biopsy–proven acute phosphate nephropathy. In clinical trials, the most commonly reported adverse reactions (reporting frequency >3%) were abdominal bloating, nausea, abdominal pain, and vomiting. It is recommended that patients receiving OSMOPREP be advised to adequately hydrate before, during, and after the use of OsmoPrep.

For complete Prescribing Information for OSMOPREP including BOXED WARNING.pdf

Important Safety Information about VISICOL

WARNINGS

There have been rare, but serious reports of acute phosphate nephropathy in patients who received oral sodium phosphate products for colon cleansing prior to colonoscopy. Some cases have resulted in permanent impairment of renal function and some patients required long-term dialysis. While some cases have occurred in patients without identifiable risk factors, patients at increased risk of acute phosphate nephropathy may include those with increased age, hypovolemia, increased bowel transit time (such as bowel obstruction), active colitis, or baseline kidney disease, and those using medicines that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and possibly nonsteroidal anti-inflammatory drugs [NSAIDs]).

It is important to use the dose and dosing regimen as recommended (PM/AM split dose).

VISICOL® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets are indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. VISICOL is not to be used in patients with congestive heart failure, ascites, unstable angina pectoris, gastric retention, ileus or acute obstruction or pseudo-obstruction, severe chronic constipation, bowel perforation, acute colitis, toxic megacolon, or hypomotility syndrome. Use with caution in patients with impaired renal function, pre-existing electrolyte disturbances, or people taking drugs that affect electrolyte levels. VISICOL is contraindicated in patients with a known allergy or hypersensitivity to sodium phosphate salts or any of its ingredients. In clinical trials, the most commonly observed (≥1%) adverse reactions occurring with use of VISICOL were generally transient and self-limited and included nausea, vomiting, abdominal bloating, abdominal pain, dizziness and headache.

Consult with your physician to see if this product is right for you.

Complete Prescribing Information for VISICOL, including BOXED WARNING pdf

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