NON ALCOHOLIC STEATO HEPATITIS (NASH)

Introduction

In some individuals there is an abnormal deposition of fat in the liver causing it to swell and enlarge. While regular alcohol consumption can bring this about in some, it may be due to other (non-alcoholic) causes in many. The spectrum of this abnormal deposition of fat in the liver (Non-Alcoholic Fatty Liver Disease or NAFLD) can rangefrom mild deposition of fat in liver (termed as steatosis in medical terminology) to active severe liver cell injury (called steatohepatitis). The importance of NASH is due to the observation that it can progress over years to liver cirrhosis and liver failure(end-stage liver disease where liver structure and function are altered to an irremediable state and liver just gradually stops working appropriately) in some patients. Hence early recognition and steps to halt and reverse the process is advisable.

What is NASH?

Non-alcoholic steatohepatitis (NASH), also known as fatty liver hepatitis, is a clinical-pathological condition that only recently has been recognized to be a common and potentially severe form of liver disease. NASH is usually defined on the basis of liver biopsy histology, characterized by accumulation of fat in hepatocytes, spotty necrosis, inflammation, Mallory bodies and fibrosis. These features resemble alcoholic liver disease, but this condition occurs in persons who drink little or no alcohol. NASH appears to be common, although its prevalence in the population is not well defined. Selected autopsy series have found fatty hepatitis in 3% of lean and up to 19% of obese subjects. NASH is most common in middle-aged persons but is found in all age groups including children. It typically occurs in persons who are overweight or diabetic, but it has recently been shown to occur in subjects with normal body weight and normal glucose tolerance. In some series, NASH has been found to be the single most common cause of serum aminotransferase abnormalities identified during routine blood testing.

What is the difference between NAFLD and NASH?

NASH is part of a group of liver diseases, known as non-alcoholic fatty liver disease or NAFLD, in which fat builds up in the liver and sometimes causes liver damage that gets worse over time (progressive liver damage). Thus it is this spectrum of abnormal deposition of fat in the liver (NAFLD) which includes and can range from plain deposition of fat in liver (termed as steatosis in medical terminology) to active severe liver cell injury (called steatohepatitis) accompanying it. Bland steatosis is rarely harmful and so it is the group comprised by NASH which concerns us more, as patients with NASH can progress to end stage liver disease. Early on, the build-up of fat does not affect the function of the liver, and you will have no symptoms. As fat continues to build up and inflammation occurs, liver function begins to decline and symptoms develop. This inflammation may lead to scarring and severe damage of the liver which leads to cirrhosis. Cirrhosis means that the liver has become scarred and hardened and is not able to work normally. There is no clear reason why some people with fatty liver develop NASH and others do not.

What are the causes of NASH?

The cause of NASH is not yet defined. Its association with obesity and diabetes suggests an underlying metabolic dysfunction, perhaps insulin resistance or inability to metabolize excess free fatty acids. However, accumulating evidence indicates that there is a second factor that ultimately leads to cell injury and inflammation in fatty liver. The suspected second 'hit' may be intracellular oxidative stress that can be induced by multiple mechanisms, such as excess iron accumulation, endotoxin exposure, pro-inflammatory cytokines or other unknown factors.

Some of the causes or associations of NASH are as follows:

* Obesity
* Diabetes
* Hyperlipidemia (increased serum Triglycerides)
* Hypo Thyroidism
* Certain drugs
* Protein-calorie malnutrition
* Starvation or rapid weight loss
* Total parenteral nutrition
* Jejunoileal bypass
* In many cases, no discernible cause is present.

What are the signs and symptoms of NAFLD and NASH and how is it diagnosed?

Many individuals with Non-Alcoholic Fatty Liver Disease (NAFLD) may have no symptoms or may experience vague abdominal discomfort. The problem may come to light during:

A routine physical examination in which the liver is detected to be enlarged.


Routine blood tests in which the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are found to be elevated.


An ultrasound examination may reveal a liver enlarged due to infiltration with fat.


Evaluation for mild symptoms like upper abdominal pain or heaviness, fatigue or dysepepsia.
The diagnosis of NASH is confirmed by liver biopsy. The histological features of the condition include macro vesicular fatty changes; parenchymal inflammation, fibrosis; and presence of Mallory hyaline bodies; cirrhosis in the late stages. The pathogenesis of NASH is unclear, but various theories have implicated free fatty acids. Although NASH is generally considered to be a benign disease, it occasionally progresses to cirrhosis with a fatal outcome.
Evaluation by tests
Once suspected to have NAFLD or NASH, the tests usually required include:



Ultrasound examination


Blood glucose levels: fasting and two hours after meals


Serum lipid profile, especially for triglycerides.


Liver function tests: Serum bilirubin (total and direct), aminotransferase (ALT/AST), albumin


Thyroid stimulating hormone (TSH)


Liver biopsy: if ALT/AST are elevated above normal (this may be an individualized decision in consultation with your gastroenterologist/hepatologist)


Tests to exclude other causes of liver disease also may be done.
What harm will it cause?

Fatty liver in most patients may not cause harm. But in some it may progress slowly over a period of 8-10 years to cirrhosis of the liver (shrunken liver). Cirrhosis is an irreversible stage and its consequences can be life threatening like blood vomits, abdominal distension with fluid, or coma. To identify those who progress to cirrhosis additional tests like liver biopsy is helpful.

Association with other diseases

NAFLD is often associated with obesity (specially the central type), diabetes mellitus, Hyperlipidemia and coronary artery disease in what is referred to as Syndrome X.

Histological findings for NASH

The diagnosis of fatty liver or NASH can be established only with a liver biopsy. Specific histological findings include:
* steatosis or presence of large droplets of fat within liver cells.
* Which usually is macro vesicular but may be micro vesicular or mixed
* inflammation that is mixed neutrophilic and mononuclear cell, portal infiltrates usually are not seen (unlike in hepatitis C)
* Mallory bodies and glycogen nuclei.
* Fibrosis or cirrhosis may be present in advanced cases.

Evaluation by test Once suspected to have NAFLD or NASH, the tests usually required include:

Ultrasound examination
Blood glucose levels: fasting and two hours after meals
Serum lipid profile, specially for triglycerides
Liver function tests: Serum bilirubin (total and direct), aminotransferase (ALT/AST), albumin
Thyroid stimulating hormone (TSH)
Liver biopsy: if ALT/AST are elevated above normal
Tests to exclude other causes of liver disease

What medical care is required?

Abstinence from alcohol may reverse steatosis in patients with alcohol-related fatty liver. Several treatment strategies have been suggested for NAFLD, which are:

Weight loss in obese patients is achieved essentially in two ways:
1. Dieting
2. Exercise

Dieting

Many people believe that to lose weight they have to go on a low-calorie diet, which according to them often means starving oneself until the diet is no longer tolerable. However, this is an incorrect approach. Weight loss should be gradual as loosing weight abruptly has been associated with progression of the disease. The first thing to realize is that changing eating habits must be more than a short-term means to an end. Changing eating habits is the cornerstone of permanent weight control. There is no way to "lose 10 kgs in two weeks" and make it last. Very-low-calorie diets cause major problems; they lower one's metabolic rate, making it harder to lose weight. The best weight control program is a high-complex-carbohydrate, low-fat, vegetarian diet complemented by regular aerobic exercise to boost up the basal metabolic rate. This is the best choice for a healthier, longer, happier life.

Calorie Chart

Some of the common food stuffs, which give 80 calories when consumed, are:
Roti (6 inches diameter)- 1
Rice 1 katori (small)
Bread 1 slice
Dals- Arhar, Mung, Urad, Chana-3/4 katori
Rajma-1/2 katori
Mutton 3 pieces
Chicken- 1 piece (breast piece)
Egg- 1
Milk (buffalo)- 1/2 cup
Milk (toned)- 1 cup
Curd- 1 cup

Fruits, which give 40 calories, are:

Apple- 1 (small)
Banana- 1 (small)
Grapes- 20
Mango- 1/2 (small)
Pineapple- 1/2 cup
Watermelon- 1 cup
Orange- 1
Guava- 2 (small)



Points to remember

1. Use low fat or no fat salad dressings. Regular dressings may have more than 10 grams of fat in one tablespoon.
2. Eat a variety of foods. Your body needs more than 40 different nutrients to stay healthy.
3. Balance the amount you eat with your activity level.

4. Steam, stir-fry or microwave vegetables. For great taste and just a few calories, spice them up with herbs, spices, lemon juice or vinegar.

5. Cutting the fat in meats is easy. Trim off as much fat as possible and remove the skin from poultry. Eat a 3-4 ounce portion, the recommended serving size, which is the size of a deck of cards.

6. Look for the words, 'Whole Wheat' or '100% Whole Wheat' on breads to get more nutrients and fiber.

7. Dried fruit, such as raisins, prunes, apricots, or apples make a great low calorie snack in the car or when you are on the go.

8. Keep healthy, crunchy foods available. Try baby carrots, fresh apples, breakfast cereals.

9. Chose skim or no fat milk. Avoid shakes like mango-shake, banana-shake and chocolate-shake, etc.

10. Stick with broth or tomato based soups to cut the fat. Cream based soups are often made with cream or whole milk that increases the fat and calorie content considerably.

11. Do not consume alcohol. It adds to the already existing liver damage.

12. Avoid fatty foods like ghee, butter and pizzas etc. as they contain saturated fats.

13. Do not take unnecessary drugs without the advice of your physician. Most of the drugs cause damage to the liver.

14. Consume large quantities of vegetables and salads like green leafy vegetables, fruits etc. They contain substances called anti-oxidants, which protect liver from damage.

15. Eat slowly! It gives your brain a chance to send the 'I am full' signal to your stomach before you overeat.

16. Resign from the 'clean plate' club. If you have had enough, leave food on your plate. Your waistline will be glad you did.
17. Learn to compensate! If you eat too many high fat foods one day or just eat too much, consider cutting back the next day.

Exercise

The key to losing weight is to use more calories than you consume. To lose 1 kg you must burn 7000 calories. The most effective way to do this is by combining both diet and exercise. Exercise regularly to loose weight. The daily work that you do is not exercise. Moreover, physical exercise can improve both your mental and physical health. Exercises can be broadly classified as:

Aerobic exercise

Aerobic exercise promotes cardiovascular fitness by raising your pulse to a targeted level and must be undertaken for atleast 30 minutes, three times a week. This strengthens your heart, and as the heart pumps more blood, prevents the build-up of fatty deposits and blood clots. Aerobic exercise also strengthens your lungs, helps control weight, and increases muscle and joint flexibility making you less susceptible to injury. Some examples of aerobic exercise are jogging, bicycling, swimming, brisk walking and aerobic dance.
An effective exercise program should include:



Warm-up - 5 minutes

A warm-up gradually increases your heart rate and the blood flow to the heart and muscles preparing them for exercise it also loosens the joints and relieves muscle spasm, thereby helping to avoid sprains. To warm-up, extremely obese patients can start by walking at a slow pace for about 5 minutes.

Aerobic Activity - 5 to 10 minutes at first, gradually increasing to 45 minutes

The term aerobic means, "using oxygen." During aerobic exercise you use oxygen to burn fat for energy. With the passage of time, gradually increase the time-span and pace of the aerobic exercise you prefer.

Cool-down - 5 minutes

Cooling down allows your heart rate, breathing and blood pressure to return to normal. It also prevents blood from pooling in your working muscles, returns it to your heart and brain, and prepares your body for stretching. To cool down, decrease your activity to

Stretching - 5 to 10 minutes

Stretching will improve your flexibility, decrease muscle soreness and help you relax. Stretch your major muscle groups, the muscles you were using for your exercise. Stretch in a relaxed, controlled manner. Hold each stretch for 20-30 seconds. Do not bounce. Your stretching should last for 5-10 minutes.

Anaerobic exercise

Anaerobic exercise promotes specific muscle size, endurance and strength. Weight lifting and using muscles against resistance (spring etc.) are examples of anaerobic exercises. This form of exercise will not provide as many benefits but is a good supplement to your aerobic workout.
Remember, there are many benefits from exercise. You will sleep better, be more alert, handle stress better and you will even look and feel better. Choose an exercise program that fits your particular needs. Weight loss in individuals who are obese may result in improvement in laboratory abnormalities, shistological findings (steatosis), and CT attenuation. The improvement usually is realized within the first 14 kgs of weight loss.

What are the benefits one can accrue from a regular exercise plan?

Remember, there are many benefits from exercise. It helps your cardiovascular system including your heart, it helps lungs, decreases weight, decreases insulin resistance, and decreases the fat all over body including that deposited in the liver.You will sleep better, be more alert, handle stress better and you will even look and feel better. Choose an exercise program that fits your particular needs. Weight loss in individuals who are obese may result in improvement in laboratory abnormalities, and histological and radiological findings (steatosis). The improvement usually is realized within the first 14 kgs of weight loss.

SOURCE:

http://www.gastroindia.in/nonalcoholicsteatohepatitis.html

IBD

Inflammatory bowel disease (IBD) is an idiopathic disease, probably involving an immune reaction of the body to its own intestinal tract. The 2 major types of IBD are ulcerative colitis and Crohn disease. As the name suggests, ulcerative colitis is limited to the colon; Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus.

Although ulcerative colitis and Crohn disease have significant differences, many (but not all) of the treatments available for one are also effective for the other. Likewise, both diseases share many extraintestinal manifestations, although some of these tend to occur more commonly with one disease or the other.

Both ulcerative colitis and Crohn disease usually have waxing and waning intensity and severity. When the patient is actively symptomatic, indicating significant inflammation, the disease is considered to be in an active stage; the patient is having a flare of the IBD.

When the degree of inflammation is less (or absent) and the patient is usually asymptomatic, then the patient's disease is considered to be in remission. In most cases, symptoms do correspond well with the degree of inflammation present for either disease, although this is not universally true. In some patients, objective evidence for disease activity should be sought before administering medications with significant adverse effects.

Pathophysiology:
The pathophysiology of IBD is under active investigation. The common end pathway is inflammation of the mucosal lining of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss.

Persons with IBD have a genetic predisposition (or perhaps susceptibility) for the disease. The triggering event for the activation of the immune response has yet to be identified. Possible factors related to this event include a pathogenic organism (as yet unidentified), an immune response to an intraluminal antigen (eg, protein from cow milk), or an autoimmune process whereby an appropriate immune response to an intraluminal antigen and an inappropriate response to a similar antigen is present on intestinal epithelial cells.

A great deal of research has been performed to discover potential genes linked to IBD. One of the early linkages discovered was on chromosome 16 (IBD1 gene), which led to the identification of the NOD2 gene (now called CARD15) as the first gene clearly associated with IBD (as a susceptibility gene for Crohn disease). Studies have also provided strong support for IBD susceptibility genes on chromosomes 5 (5q31) and 6 (6p21 and 19p). NOD2/CARD15 is a polymorphic gene involved in the innate immune system. The gene has more than 60 variations. Three of these variations play a role in 27% of patients with Crohn disease, primarily in patients with ileal disease. One important point to note with all of these potential genes is that they appear to be permissive (ie, allow IBD to occur) but not causative (ie, just because the gene is present does not necessarily mean the disease will develop).

None of these mechanisms has been implicated as the primary cause, but they are postulated as potential causes. The lymphocyte population in persons with IBD is polyclonal, making the search for a single precipitating cause difficult. In any case, activation of the immune system leads to inflammation of the intestinal tract, both acute (neutrophilic) and chronic (lymphocytic, histiocytic).

Many of the mucosal changes seen in persons with IBD are nonspecific in nature; they are seen in any organ system in which active inflammation is occurring. Many inflammatory mediators have been identified; antibodies against these mediators or methods to block the production or receptors for these mediators hold great promise for potential therapy for IBD.

Frequency:
In the US: Approximately 1 million people in the United States have ulcerative colitis or Crohn disease. Before 1960, the incidence of ulcerative colitis was several times higher than that of Crohn disease. The latest data suggest that the current incidence of Crohn disease is approaching that of ulcerative colitis, although this change may reflect improved recognition and diagnosis of Crohn disease.


In the United States, the rates of IBD among persons of European descent have been measured in Olmstead County, Minn. In this population, the incidence of ulcerative colitis is 7.3 cases per 100,000 people per year and the prevalence is 116 cases per 100,000 people; the incidence of Crohn disease is 5.8 cases per 100,000 people per year and the prevalence is 133 cases per 100,000 people.

The prevalence of IBD among Americans of African descent is estimated to be the same as the prevalence among Americans of European descent. The prevalence is lower among Americans of Asian and Hispanic descent.

Internationally: The incidence of IBD is assumed to be highest in developed countries and lowest in the developing regions of the world. A recent study in Italy showed the incidences of ulcerative colitis and Crohn disease to be similar to those found in the United States. Persons living in colder climates have a greater rate of IBD than persons living in warmer climates. Persons living in urban areas have a greater rate of IBD than persons living in rural areas.


Mortality/Morbidity:
Multiple studies have been conducted from regions throughout the world on mortality in patients with IBD. The mortality from ulcerative colitis has decreased over the past 40-50 years.

One study suggested decreased mortality for ulcerative colitis (standardized mortality ratio of 0.6 in Florence, Italy), but the vast majority of studies indicate a small but significant increase in mortality associated with IBD. The standardized mortality ratio for IBD generally ranges from approximately 1.4 times the general population (Sweden) to 5 times the general population (Spain). In general, the 95% confidence intervals suggest that the increase in relative risk is real. Ulcerative colitis and Crohn disease have approximately equal mortality rates.


The most frequent cause of death in persons with IBD is the primary disease, followed by malignancy and thromboembolic disease.


A generally accepted postulation is that the risk of colorectal cancer is not significantly higher in persons with ulcerative colitis compared with the general population until several years after diagnosis. Beyond 8-10 years after diagnosis, the risk of colorectal cancer increases by 0.5-1.0% per year. Recent data suggest that surveillance colonoscopies with random biopsies reduce mortality from colorectal cancer in patients with ulcerative colitis, primarily by allowing the detection of carcinoma at an earlier Duke stage. Recent data suggest that persons with Crohn colitis involving the entire colon have a risk of developing malignancy equal to that of persons with ulcerative colitis; however, the risk for most patients with Crohn disease is much smaller (albeit poorly quantified).


Race: The incidence of IBD has been reported to be highest in Jewish populations, followed by non–Jewish white populations. However, more recent data suggest that incidences in non-Jewish, black, and Hispanic populations are increasing. The American Jewish population has one of the highest prevalences of IBD, 4-5 times that of the general population.

Sex: The male-to-female ratio is approximately equal for both ulcerative colitis and Crohn disease.

Age: Ulcerative colitis and Crohn disease are diagnosed most commonly in young adults (ie, late adolescence to the third decade of life). The age distribution of newly diagnosed IBD cases is bell-shaped; the peak incidence occurs in people in the early part of their second decade of life, with the vast majority of new diagnoses made in people aged 15-40 years. However, children younger than 5 years and elderly persons are occasionally diagnosed. Of patients with IBD, 10% are younger than 18 years.

History: The manifestations of IBD generally depend on the area of the intestinal tract involved. Patients with ulcerative colitis or Crohn colitis frequently have bloody diarrhea, occasionally with tenesmus. Patients with Crohn disease involving the small intestine frequently have abdominal pain and diarrhea, and occasionally they have symptoms of intestinal obstruction. A variety of intestinal and extraintestinal manifestations of IBD also may be observed in conjunction with either ulcerative colitis or Crohn disease.

Ulcerative colitis

The most typical manifestation of ulcerative colitis is bloody diarrhea. Pain is uncommon but may occur.


Patients are commonly fatigued, which is often related to the inflammation and anemia that accompany disease activity.


Crohn disease

The most typical manifestations of Crohn disease are abdominal pain and diarrhea. Not uncommonly, patients have been diagnosed with irritable bowel syndrome before being diagnosed with IBD.


Pain is particularly common, especially when some degree of obstruction is present. The pain may be almost anywhere within the abdominal cavity, although the classic location is the lower abdomen or right lower quadrant (appendicitislike).


Patients are commonly fatigued, which is often related to the pain, inflammation, and anemia that accompany disease activity.


Intestinal complications

Strictures and obstructions are not uncommon in persons with Crohn disease These strictures are often inflamed and frequently resolve with medical treatment. Fixed (scarred or cicatrix) strictures may require endoscopic or surgical intervention to relieve obstructions. However, in persons with ulcerative colitis, colonic strictures are of significant concern and should be presumed to be malignant unless proven otherwise (usually by resection).


Fistulae and perianal disease are not uncommon in persons with Crohn disease and may be refractory to vigorous medical treatment, including antibiotic therapy Surgical intervention is often required for fistulae and perianal disease treatment, but both are associated with a high risk of recurrence.


Toxic megacolon is a life-threatening complication of ulcerative colitis and requires urgent surgical intervention.


Infectious colitis is in the differential diagnosis of ulcerative colitis and must be excluded before the diagnosis of ulcerative colitis can be made. However, in patients with well-established ulcerative colitis, superimposed infection can occur. Infection with Clostridium difficile is by far most common. Stools of patients hospitalized for a flare of ulcerative colitis should be tested for C difficile toxin. Treatment of C difficile (if present) infection generally helps put the flare into remission.


Malignancy is the most dreaded long-term intestinal complication of ulcerative colitis. The risk of colon cancer for persons with ulcerative colitis begins to rise significantly above that of the general population approximately 8-10 years after diagnosis. For cancer prevention, surveillance colonoscopy every 2 years after 8 years of disease is recommended, more frequently if areas of pathologic concern are evident. The risk of cancer in persons with Crohn disease may equal to that of persons with ulcerative colitis if the entire colon is involved, and screening may be beneficial for patients with pancolitis Crohn disease. The risk of small intestine malignancy is increased in persons with Crohn disease, but the malignancy is as likely to arise in a previously normal area as in an inflamed area. No screening protocol has ever been demonstrated to be effective for small bowel Crohn disease.


Physical:
Ulcerative colitis

Presenting signs of ulcerative colitis include diarrhea with occult or frank blood loss .Weight loss and anemia are also common. Persons with ulcerative colitis typically do not develop fistulae or perianal disease, although they may have perianal abscesses.


Diagnosis can be made endoscopically or radiologically, with contrast radiographs typically showing loss of the normal mucosal pattern and, with more advanced disease, loss of colonic haustrae.


Sigmoidoscopy or colonoscopy reveals that the rectum is almost always involved. The disease can be limited to the rectum (proctitis); to the rectum, sigmoid, and descending colon (left-sided colitis); or to the entire colon (pancolitis). Ulcerative colitis does not involve any other segment of the gastrointestinal tract. Colectomy is curative.


Crohn disease

Presenting signs of Crohn disease include occult blood loss and low-grade fever; weight loss and anemia are common. Growth retardation is seen in children and may be the only presenting sign in young patients. Fistulae and perianal disease are not uncommon.


Diagnosis can be made endoscopically or radiologically, with contrast radiographs typically showing a cobblestone pattern to the mucosa and areas of normal mucosa alternating with areas of inflamed mucosa (skip lesions).


Sigmoidoscopy or colonoscopy reveals that the rectum is frequently spared and right colonic predominance is common. Occasionally, gastric or duodenal Crohn disease manifests as seemingly refractory ulcer disease.


Extraintestinal complications:
Many complications associated with IBD can occur with either ulcerative colitis or Crohn disease. In addition, many of the medications used to treat IBD may cause significant adverse systemic effects.


In addition to medication-induced arthropathies, the arthritides associated with the IBD are of 2 varieties, axial (or central) arthritis and peripheral arthritis.

The axial arthritis associated with IBD consists of ankylosing spondylitis and sacroiliitis. Axial arthritis occurs in approximately 5% of patients with IBD (often Crohn disease) and typically is independent of disease activity. Axial arthritis is often associated with HLA-B27.

The peripheral arthritides vary with the activity of the underlying IBD. Peripheral arthritis occurs in approximately 10% of patients with IBD; it is a nondestructive arthritis, and patients have seronegative findings for rheumatoid factor. The peripheral arthritis typically is asymmetric, and it can be monoarticular or may involve different joints on different sides of the body. The classic peripheral arthritis affects large weight-bearing joints, although any joint may be involved.


Diseases of the eye associated with ulcerative colitis are episcleritis and iritis (uveitis). Treatment of these complications often requires high-dose systemic steroids or infliximab, and either condition can cause significant vision loss if left untreated.

The major skin diseases associated with IBD are erythema nodosum and pyoderma gangrenosum.

Erythema nodosum is a painful, tender, raised, purplish lesion on the anterior surface of the tibia. Erythema nodosum tends to correlate well with the activity of the underlying bowel disease; with bowel disease treatment, the erythema nodosum usually dissipates.

Pyoderma gangrenosum, on the other hand, typically is not associated with disease activity .This skin lesion starts as an inflamed patch of skin ranging from one to several centimeters in diameter that progresses until it ulcerates. Upon ulceration, the lesion may persist for many months before healing. Treatments that have been tried that may have some efficacy include dapsone, metronidazole (MetroGel), cyclosporine, and infliximab. Surgical removal of the diseased bowel (eg, colectomy) does not ameliorate pyoderma gangrenosum.

Infectious skin lesions related to immune suppression may also be seen (eg, herpetic lesions)


The urinary complications of IBD are more common in persons with Crohn disease. Calcium oxalate stones are the most common type of renal calculi associated with Crohn disease; treatment is to increase hydration and to use oral calcium citrate supplements, which bind the oxalate within the intestinal tract and prevent its excretion in the urinary tract. Because of its proximity to the ureters, inflammation of the small bowel may involve the ureters, causing obstruction and hydronephrosis. Fistulae occasionally occur between the bowel and bladder or ureters.


Sclerosing cholangitis is most commonly associated with ulcerative colitis. Sclerosing cholangitis is a disease of the biliary tree. Although sclerosing cholangitis typically manifests as fatigue and, perhaps, jaundice, it is far more commonly sought when abnormal LFT results in a cholestatic pattern are found in a patient with ulcerative colitis.

Although ursodeoxycholic acid may help improve serum LFT results, this has not been translated into improved survival. If sclerosing cholangitis is diagnosed in the absence of a known history of ulcerative colitis, colonoscopy is indicated.

Ulcerative colitis may be expected to be clinically evident within 2 years of diagnosis of sclerosing cholangitis if the colitis is present and has not been diagnosed first. Sclerosing cholangitis may be indolent for many years but may progress to cirrhosis, for which hepatic transplantation may be necessary. The most dreaded complication of sclerosing cholangitis is the development of cholangiocarcinoma.


Gallstones are common in persons with Crohn disease, but these persons are usually asymptomatic; occasionally, cholecystectomy is necessary.


The anemia associated with IBD may be of 2 types, (1) iron deficiency anemia secondary to chronic blood loss and (2) anemia of chronic disease. Because iron is absorbed in the duodenum, patients with Crohn disease involving the proximal small intestine may have difficulty absorbing oral iron; occasionally, parenteral iron replacement is necessary. IBD is a recognized cause of anemia of chronic disease.


A hypercoagulable state is associated with IBD. It is estimated to occur in as many as one third of patients with IBD, but it may go unrecognized until a thrombotic event occurs. Strokes, retinal thrombi, and pulmonary emboli are not uncommon in patients with IBD.


Causes: The causes of IBD are currently unknown.

Genetics: IBD clearly has a familial tendency. A parent with IBD has approximately a 4% chance of having a child develop IBD. Of patients with IBD, 10-25% are estimated to have a first-degree relative with the disease. Monozygous twin studies show a high concordance for Crohn disease but less so for ulcerative colitis.


Animal models: Several animal models are used to study IBD. A local irritant (eg, acetic acid, trinitrobenzene sulfonic acid) can be inserted via an enema into the colon of rats or rabbits to induce a chemical colitis. An interleukin-10 knockout mouse has been genetically engineered to have some characteristics similar to those of a human with IBD.

The cotton-top marmoset, a South American primate, develops a colitis very similar to ulcerative colitis when the animal is subjected to stress.

Differentials:

Anorexia Nervosa
Appendicitis
Bulimia
C1 Esterase Deficiency
Celiac Sprue
Chronic Pelvic Pain
Clostridium Difficile Colitis
Collagenous and Lymphocytic Colitis
Cytomegalovirus
Cytomegalovirus Colitis
Depression
Diverticulitis
Eosinophilic Gastroenteritis
Food Poisoning
Gastroenteritis, Bacterial
Gastroenteritis, Viral
Giardiasis
Intestinal Motility Disorders
Intestinal Radiation Injury
Irritable Bowel Syndrome
Lactose Intolerance
Perianal Abscess
Salmonellosis
Sarcoidosis
Ulcerative Colitis

Other Problems to be Considered:
Intestinal tuberculosis
Estrogens
Backwash ileitis


Lab Studies:
Laboratory studies are of value in assisting with the management of IBD but are of minimal help in establishing the diagnosis. Laboratory values may be used as surrogate markers for inflammation and nutritional status and to look for deficiencies of necessary vitamins and minerals. Serologic studies have been proposed to help diagnose IBD and to differentiate Crohn disease from ulcerative colitis.


Stool studies: Perform a stool culture (and C difficile toxin assay) on patients before making a definitive diagnosis of idiopathic IBD. Any patient hospitalized with a flare of colitis should, at a minimum, have a C difficile toxin assay performed because, commonly, pseudomembranous colitis is superimposed on ulcerative colitis.


Complete blood cell count: The components of the CBC count can be useful indicators of disease activity and iron or vitamin deficiency. An elevated WBC count is common in patients with active inflammatory disease and does not necessarily indicate infection. Anemia is common and may be either an anemia of chronic disease (usually normal mean corpuscular volume [MCV]) or an iron deficiency anemia (MCV is often low). Generally, the platelet count is normal, or, it may be mildly to moderately elevated if active inflammation is occurring, particularly if gastrointestinal blood loss occurs. Note that the MCV can be elevated in patients taking azathioprine (Imuran) or 6-mercaptopurine (6-MP).


Erythrocyte sedimentation rate: The erythrocyte sedimentation rate (ESR) is used as a surrogate marker for inflammation; an elevation above normal generally indicates the presence of an inflammatory response. For most, but not all, patients, the ESR can be used to help determine whether active IBD is present. Persons with cicatrix strictures are not expected to have an elevated ESR.


Nutritional markers: Blood tests can also be used to help determine nutritional status. The most commonly used marker is serum albumin; prealbumin and transferrin can also be used, although the latter is an acute phase reactant and can be falsely elevated in persons with active IBD. Hypoalbuminemia may reflect malnutrition; it can also develop because of the protein-losing enteropathy that can occur with active IBD.


Serum vitamin B-12: Vitamin B-12 deficiency can occur in patients with Crohn disease who have significant terminal ileum disease or in patients who have had terminal ileum resection. The standard replacement dose of vitamin B-12 is 1000 mcg subcutaneously every month.


Serum iron studies: Because active IBD is a source for gastrointestinal blood loss, iron deficiency is common. A microcytic hypochromic anemia suggests iron deficiency; if confirmed with serum iron/total iron-binding capacity, iron can be replaced either enterally or parenterally. For parenteral replacement, intravenous iron dextran can be used and is dosed based on the table in the package insert, with a maximum of 30 mL (1500 mg) at once.


Red blood cell folate: While folate deficiency is not common in persons with IBD, several concerns have been raised regarding this vitamin. Sulfasalazine (Azulfidine) is a folate reductase inhibitor and may inhibit normal uptake. Although some practitioners administer folate supplements in patients taking sulfasalazine, few data demonstrate that this is universally necessary. Folate supplements are indicated in all women who are pregnant to help prevent neural tube defects; this is particularly true for patients with IBD, and supplementation with 2 or more mg/d (rather than the usual 1 mg/d) should be considered.


Imaging Studies:
Abdominal flat plate: For the patient with IBD, kidneys, ureter, bladder radiography can provide a great deal of information. Evidence of obstruction can be seen. Evidence of inflammatory disease, especially involving the colon, can often be discerned, perforation can be detected, and toxic megacolon can be diagnosed. More subtle findings can include indications of osteopenia and nephrolithiasis.


Barium enema: This was one of the first studies that allowed characterization of the typical findings associated with IBD. Normal barium enema findings virtually exclude active ulcerative colitis, whereas abnormal findings can be diagnostic. Several terms have been used to describe abnormalities found after barium studies of the colon. These include (1) a “stove-pipe” appearance, which suggests chronic colitis that has resulted in a loss of colonic haustrae; (2) “rectal sparing,” which suggests Crohn colitis in the presence of inflammatory changes in other portions of the colon; (3) “thumbprinting,” which indicates mucosal inflammation (which can also be seen frequently on the abdominal flat plate); and (4) “skip lesions,” which suggests areas of inflammation alternating with normal-appearing areas, again suggesting Crohn colitis. Barium can be refluxed into the terminal ileum in many cases, which can assist in the diagnosis of Crohn disease.


Small bowel series/small bowel follow-through: The small bowel series, with or without an upper gastrointestinal tract series, provides invaluable information about Crohn disease. This study can reveal if inflammation is present, can assist in the assessment of stricture length and severity, and can help decide the most appropriate surgical approach. Fistulae are often demonstrated on films from a small bowel series, even if they are not suggested based on the clinical evaluation. The small bowel series is usually sufficient for the evaluation of small intestine Crohn disease; rarely, it affords an inadequate view of the terminal ileum and enteroclysis must be performed. Although radiologists may remark on abnormalities suggested in the cecum or ascending colon when the barium from a small bowel series enters the colon, independent confirmation must be sought because the presence of stool and dilution of the barium make proper interpretation of colon findings difficult.


Small bowel enteroclysis: The enteroclysis differs from a small bowel series in that a nasoenteric or oroenteric tube is placed and contrast is instilled directly into the small intestine. This is usually performed when fine detail of the intestinal mucosa is required or the distal small intestine is not adequately seen on the small bowel series because the contrast is diluted as it passes through the (usually dilated) small bowel.


Computed tomography scan of the abdomen and pelvis: CT scanning of the abdomen and pelvis has limited use in the diagnosis of IBD, but findings may be very suggestive of IBD. Wall thickening on CT scans is nonspecific and may occur from smooth muscle contraction alone, especially in the absence of other extraintestinal inflammatory changes; however, the presence of inflammatory changes significantly increases the predictive value of the CT scan. CT scanning is the ideal study to determine if the patient has abscesses, and it can be used to guide percutaneous drainage of these abscesses. Fistulae also may be detected on CT scans.


Fistulogram: Contrast can also be inserted directly into an enterocutaneous fistula in order to help determine the course of the fistula in anticipation of surgical correction and to assist in guiding the surgical approach.


Procedures:
Colonoscopy

This is one of the most valuable tools available to the physician for the diagnosis and treatment of IBD, although its limitations must be recognized. Foremost, not all mucosal inflammation is idiopathic IBD. Infectious causes of inflammation must always be considered, as should diverticulitis and ischemia (which are far more common as new diagnoses in an elderly population than IBD, despite the similar colonoscopic and histologic appearance).

When used appropriately, colonoscopy can help determine the extent and severity of colitis, assist in guiding treatment, and provide tissue to assist in the diagnosis. In skilled hands, the colonoscope can frequently reach the terminal ileum and permit assessment of inflammation to assist in the diagnosis or exclusion of Crohn disease. Inflammation may occasionally occur in the terminal ileum in patients with ulcerative colitis; this is referred to as a backwash ileitis and is mild, nonulcerating, and may occur when a widely patent ileocecal valve is present.

Be cautious with colonoscopic intervention in patients with IBD. The usual risks of colonoscopy apply (eg, reaction to medication, bleeding, perforation); the risk of bleeding is increased in the presence of inflammation, and even mucosal biopsies may require cautery to limit bleeding. The risk of perforation is also increased, particularly in patients taking high doses of steroids long-term. Also, weigh the risks and benefits of continuing colonic intubation in a patient with IBD who has significant inflammation.

Colonoscopy can also be used for therapeutic intervention in patients with IBD. The most common therapeutic use is stricture dilation in persons with Crohn disease; colonic, anastomotic, and even small bowel strictures can often be dilated using pneumatic through-the-scope dilators. Intralesional injection of steroids (eg, triamcinolone at 5 mg in 4 quadrants) may help prevent reformation of the stricture, although this has yet to be demonstrated in controlled trials.


Flexible sigmoidoscopy:
This study is useful for a preliminary diagnosis in patients with chronic diarrhea or rectal bleeding; however, because of the limited length of the scope (60 cm), it can only help diagnose distal ulcerative colitis or proctitis, but not pancolitis. Rarely, Crohn colitis can be diagnosed based on flexible sigmoidoscopy findings; use caution interpreting sigmoid inflammation, particularly in older patients, because Crohn colitis may be confused with diverticulitis or ischemia.


Upper endoscopy:
Esophagogastroduodenoscopy is used for the evaluation of upper gastrointestinal tract symptoms, particularly in patients with Crohn disease. Aphthous ulceration occurs in the stomach and duodenum in 5-10% of patients with Crohn disease. The diagnosis of Crohn disease is occasionally made after gastric or duodenal ulcers fail to heal with acid suppression alone.


Small bowel enteroscopy:
This is of limited use in patients with Crohn disease and is of almost no value in those with ulcerative colitis. Although ulcerations and strictures in the upper half of the jejunum can be demonstrated with enteroscopy, the same information (and often more information) can be demonstrated on the small bowel follow-through x-ray film.


Histologic Findings:
In ulcerative colitis, the inflammation is limited to the mucosa. Inflammation almost always involves the rectum and is contiguous, virtually regardless of the extent of the colon involved. The exception to this rule is that the initial inflammation may appear patchy during colonoscopy performed very early in the ulcerative colitis process, although biopsy specimens of intervening normal-appearing mucosa often do reveal inflammation. The intestinal inflammation of ulcerative colitis only involves the colon; the remainder of the gastrointestinal tract is not inflamed. Biopsy specimens demonstrate neutrophilic infiltrate along with crypt abscesses and crypt distortion. Granulomas do not occur in ulcerative colitis.


The entire intestinal wall is involved with inflammation in Crohn disease, not just the mucosa, as in ulcerative colitis. Biopsy specimens frequently demonstrate granulomas (approximately 50% of the time). The presence of granulomas is often helpful for making the diagnosis but is not necessary.

Because biopsy specimens obtained at colonoscopy are generally superficial mucosal tissue samples, the pathologist often has difficulty making a definitive diagnosis of ulcerative colitis or Crohn disease based on histologic findings alone. However, other causes of inflammation may be suggested based on pathology findings (eg, infectious colitis).


Medical Care:
The care of a patient with IBD can be either medical or surgical in nature. The medical approach for patients with IBD is symptomatic (flaring) care and generally follows a step-wise approach to medication therapy, with progression of the medical regimen until a response is achieved. Whether patients whose disease is in remission benefit from continuing to take aminosalicylate is controversial. In persons with Crohn disease, earlier data suggested that postoperative recurrences are decreased in frequency and severity, although later data suggest that this preventive effect may not apply to flares of this IBD.

The first step in medication therapy is usually aminosalicylates; no advantage has been demonstrated for any particular agent for either ulcerative colitis or Crohn disease. For Crohn disease, metronidazole or ciprofloxacin is occasionally used, particularly for perianal disease or an inflammatory mass.


If the IBD fails to respond to aminosalicylates, the second step is corticosteroids. Corticosteroids tend to provide rapid relief of symptoms and a significant decrease in inflammation, but they are limited by their adverse effects, particularly for prolonged use.

The consensus regarding treatment with corticosteroids is that they should be tapered as rapidly as possible. Corticosteroids do not have a role in maintaining remission.


If patients have difficulty reducing the dose of corticosteroids, have IBD that is refractory to corticosteroid therapy, or have frequent flares that require corticosteroid therapy, the third step for medication is one of the immunomodulatory agents, either 6-MP or azathioprine.

These agents are not used for acute flares because the time from the initiation of treatment to the onset of significant action may be as long as 2-3 months. Response to these agents may be dose dependent; monitoring of blood counts is required to protect the patient from the hematological toxicity associated with these agents. Some authors suggest earlier use of these agents.

An alternative third step is available for persons with Crohn disease. This alternative is infliximab, a monoclonal antibody against tumor necrosis factor (TNF)–alpha. Administer this agent by intravenous infusion. It may occasionally be given as a single dose or, more commonly, 3 doses (for fistulizing Crohn disease) followed by a maintenance regimen. Administering the drug every 8 weeks has been demonstrated to be effective for maintaining remission. The practitioner is advised to have the patient seek insurance approval for the administration of this medication because it is extremely expensive (typically, several thousand dollars per dose). As of this writing, the medications approved by the US Food and Drug Administration for the treatment of Crohn disease are prednisone, budesonide, and infliximab.


The final step for the treatment of IBD involves agents that have less well-demonstrated levels of efficacy but have been shown to be useful in some subsets of patients. For Crohn disease, methotrexate at 12.5-25 mg/wk may fall into this category. For ulcerative colitis, cyclosporine A (usually started intravenously for overwhelming disease) and nicotine patches fall into this category. Finally, a number of clinical trials of biological agents and diets are being conducted and may demonstrate efficacy in persons with IBD.


Surgical Care:
The approach to surgical treatment of IBD varies depending on the disease. Importantly, ulcerative colitis is a surgically curable disease because the disease is limited to the colon.

However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; thus, surgical resection is not curative. On the contrary, excessive surgical intervention can leave the patient with a crippling short bowel syndrome.

Situations arise in Crohn disease in which surgical intervention without resection can be used to defunctionalize the colon in order to possibly allow healing of distal disease.

Surgery for ulcerative colitis

Surgical intervention for ulcerative colitis is curative for colonic disease and potential colonic malignancy. The indications for colectomy are (1) inflammation that is difficult to control, (2) early changes found during surveillance (high-grade dysplasia, low-grade dysplasia in some instances), (3) strictures; (4) significant adverse medication effects, and/or (5) an unacceptable quality of life referable to the ulcerative colitis.


The surgical options for ulcerative colitis vary. While segmental resection is rarely performed, total proctocolectomy is common. Total proctocolectomy with ileostomy creation is the simplest procedure with the lowest overall complication rate. A variation on this is the continent ileostomy or Koch pouch. This procedure creates an ileal reservoir that can be emptied with catheterization several times per day. However, incontinence from the pouch may necessitate use of an ileostomy bag. A colectomy may be performed, leaving a few centimeters of rectum intact; this ensures anal continence, but continued malignancy surveillance is needed for any colonic mucosa that remains and the remaining diseased rectal mucosa can continue to be problematic from a symptomatic standpoint.


The most technically demanding option is ileoanal anastomosis. In this multistage procedure, a diverting ileostomy is performed and an ileal pouch is created and anastomosed directly to the anus, with complete removal of the rectal mucosa. After the ileoanal anastomosis is healed, the ileostomy is taken down and flow through the anus is reestablished. The major complications of this procedure are anal incontinence and impotence. Pouchitis occasionally is a problem. If the diagnosis is incorrect and this procedure is performed on a patient with colonic Crohn disease, the likelihood of disease recurrence at the ileoanal anastomosis is high, which requires takedown, ileostomy creation, and loss of additional small bowel. When performed by a surgeon skilled in this technique, it offers an excellent option for younger patients with ulcerative colitis and concerns about body image.


Surgery for Crohn disease

The most straightforward surgery for Crohn disease is the segmental resection, in which a segment of intestine with active Crohn disease or a stricture is resected and the remaining bowel is reanastomosed. This surgery requires margins of resection; in general, as little bowel as possible is resected because the risk of disease recurrence is significant.

In patients with a very short cicatrix (scar tissue) stricture, a bowel-sparing stricturoplasty can be performed. In this procedure, a longitudinal incision is made across the stricture and then the incision is repaired with a vertical suture. All mucosa is spared, and the obstruction is relieved. As many as 6-8 stricturoplasties can be performed in a single operative session. Stricturoplasty is associated with a 6-8% septic complication rate (2-3% of patients require reoperation); this can generally be prevented with optimal preoperative management to control the inflammatory component of the stricture before surgical intervention.


Ileorectal or ileocolonic anastomosis is an option available to some patients who have distal ileal or proximal colonic disease. This is a variation on the simple segmental resection.

In patients with severe perianal fistulae, a diverting ileostomy or colostomy is a surgical option. In this procedure, the distal colon is defunctionalized and a temporary ileostomy or colostomy is created. The defunctionalized rectum is allowed to heal, and the ileostomy or colostomy is then taken down 6 months or a year later. Many patients who pursue this option choose to forego reanastomosis after experiencing a stoma and a consequent improvement in quality of life. Approximately 50% of patients who have the reanastomosis performed have recurrences of perianal disease.


Consultations:
In addition to possible studies performed by an endoscopist or radiologist, patients with IBD who are admitted to a medical service facility typically require consultation with a surgeon.

Colorectal surgeon (where available) or general surgeon: Early consultation with a surgeon is particularly useful in patients with stricturing or fistulizing disease and in patients with ulcerative colitis who experience frequent flares, have significant adverse effects from medications, or have an unacceptable quality of life.


Radiologist: An interventional radiologist may be consulted when percutaneous drainage of an abscess is desired.


Diet: No known dietary substances cause activation of IBD. Diet may influence intestinal inflammation in persons with Crohn disease, but it does not play a role in influencing inflammation in those with ulcerative colitis.

Lactose intolerance is common in persons with Crohn disease or ulcerative colitis and some patients with other types of IBD.


Diet has been well demonstrated to have little or no influence on inflammatory activity in persons with ulcerative colitis. However, diet may influence symptoms. For this reason, patients are often advised to make a variety of diet modifications, especially the adaptation of a low-residue diet. Evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis, although it might decrease the frequency of bowel movements.


Unlike in persons with ulcerative colitis, diet can influence inflammatory activity in persons with Crohn disease. Nothing by mouth (status NPO) can hasten the reduction of inflammation, as might the use of a liquid or predigested formula for enteral feeding.

Although a meta-analysis in 1993 demonstrated that steroids were superior to liquid diet alone for Crohn disease, a liquid diet seemed superior to a regular diet for reducing inflammation. The problem with using enteral liquid diets, especially the predigested formulations, is that palatability limits the intake of adequate energy (calories) to meet patient requirements. Parenteral alimentation may be needed.


Activity: Generally, patients do not need to limit activity when IBD is quiescent. Even during flares of disease activity, activity is limited only by the extent of fatigue and the abdominal pain or diarrhea the patient is experiencing.

Abdominal pain may limit the ability of the patient to work productively during flares of disease. When abdominal pain persists beyond medical therapy–induced resolution of the active inflammation, other causes of pain must be considered, including nephrolithiasis, abscess, stricture, irritable bowel syndrome, and psychiatric disease.


In most instances, diarrhea limits activity primarily because of the lack of immediate access to toilet facilities in many locations and/or occupations. This can often be resolved with employers. Occasionally, dehydration may be an issue, requiring intravenous hydration or the use of oral rehydration solutions.


Medications:
While several drugs have been used successfully for the treatment of IBD for many years, medical treatment has advanced rapidly. The medications used are broken down into several classes based on the chemical similarities of the individual agents and similarities in the mechanisms of action. A step-wise approach may be taken. With this approach, the most benign (or temporary) drugs are used first. As they fail to provide relief, drugs from a higher step are used.

The aminosalicylates and symptomatic agents are step I drugs under this scheme; the antibiotics are a step IA, given the limited situations in which they are used. The corticosteroids constitute the step II drugs to be used if the step I drugs fail to adequately control the IBD. The immune-modifying agents are step III drugs and are used if corticosteroids fail or are required for prolonged periods. Infliximab is also a step III drug and is used in limited situations in patients with Crohn disease. The experimental agents are step IV drugs and are used only after the previous steps fail and, then, are administered only by physicians familiar with their use.

Note that drugs from all steps may be used additively; in general, the goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Opinions differ regarding the use of certain agents in this step-wise approach.

Step I (aminosalicylates)

The 5 oral aminosalicylate preparations available for use in the United States are sulfasalazine (Azulfidine), mesalamine (Asacol, Pentasa), balsalazide (Colazal), and olsalazine (Dipentum). Enema and suppository formulations are also available. All of these are derivatives of 5-aminosalicylic acid (5-ASA); the major differences are in the mechanism of delivery. Some of these also have unique adverse effects that other agents of this class lack. All of the aminosalicylates are useful for treating flares of IBD and for maintaining remission. None of the aminosalicylates has been proven to have greater efficacy for the treatment of ulcerative colitis or Crohn disease over any of the others. All of them are clearly more effective in persons with ulcerative colitis than in persons with Crohn disease; in persons with Crohn disease, the primarily utility is for colonic disease.

Step IA (antibiotics)
The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with IBD. Antibiotics are used only sparingly in persons with ulcerative colitis because ulcerative colitis increases the risk of developing antibiotic-associated pseudomembranous colitis. When used in persons with ulcerative colitis, antibiotics are most commonly administered in the perioperative setting. However, in persons with Crohn disease, antibiotics are used for a variety of indications, most commonly for perianal disease. They are also used for fistulae and inflammatory masses in the abdomen, and they may have some efficacy in treating ileitis. The antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections; peripheral neuropathy can be observed in association with metronidazole use and, when present, requires discontinuation of therapy with that drug.

Step II (corticosteroids)

Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of IBD. Indications are for acute flares of disease only; corticosteroids have no role in the maintenance of remission. Corticosteroids may be administered by a variety of routes depending on the location and severity of disease; they may be administered intravenously (ie, methylprednisolone, hydrocortisone), orally (ie, prednisone, prednisolone, budesonide, dexamethasone), or topically (ie, enema, suppository, or foam preparations).

Intravenous corticosteroids are often used for patients who are severely ill and hospitalized; few data have been published on the optimum dosage of intravenous (or oral form) corticosteroids. The generally used upper ends of dosing are methylprednisolone at 40 mg intravenously every 6 hours or hydrocortisone at 100 mg intravenously every 8 hours. Some situations mandate a higher initial intravenous dose, but many practitioners start hospitalized patients at lower intravenous doses.

In general, once a clinical response is observed (typically within a 1-2 d, occasionally longer), the dose of the intravenous corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made; further dosage tapering can be accomplished in an outpatient setting. When oral corticosteroids are used, dosing is highly variable and few data have been published to guide optimal dosing. The most common range for moderate flares of IBD is prednisone at 10-40 mg/d; for more severe flares, the higher end of the range is used (occasionally even higher doses are used). Again, once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can only occasionally tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse. When the latter situation occurs, consider the use of alternative drugs (immune modifiers or anti-TNF therapy).

Topical corticosteroids are used in persons with distal colonic disease in a manner similar to topical mesalamine; the major difference is that even though topical mesalamine may be used to help maintain remission, topical corticosteroids are used for active disease and have only a small role in the maintenance of remission. The potential complications of corticosteroid use are multiple and include fluid and electrolyte abnormalities, osteoporosis, aseptic necrosis, peptic ulcers, cataracts, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis). Patients who are taking corticosteroids, especially for longer than a few weeks, must be warned about the associated complications; this discussion should be documented in the medical record. Some recent data assert that some agents used for osteoporosis prevention and treatment (eg, the bisphosphonates) are useful for preventing the bone loss associated with corticosteroid use.

Step III (immune modifiers)

The immune modifiers 6-MP and azathioprine are used in patients with IBD in whom remission is difficult to maintain with the aminosalicylates alone. Immune modifiers work by causing a reduction in the lymphocyte count, and because of that mechanism of action, their onset of action is relatively slow (typically 2-3 mo). They are used most commonly for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulae and the maintenance of remission in patients intolerant of aminosalicylates. Use of these agents mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that would warrant a dose reduction or discontinuation. Routine CBC counts with differentials and platelet counts are checked monthly, and LFTs can be performed intermittently. After a year of stable dosing with no difficulties with blood counts (except the expected lymphopenia), the intervals between blood count monitoring can be increased.

The cytopenic effect is typically dose dependent, although some patients are more sensitive than others. Typical dosing of the immune modifiers (either 6-MP or azathioprine) is 1-2 mg/kg/d. If needed, the dose can be increased to the point when cytopenia occurs; obviously, at higher doses, closer monitoring is warranted. Blood tests are available to measure metabolite levels, but the results have not been shown in independent studies to have any correlation with clinical efficacy. These blood tests for monitoring toxicity offer little advantage (but much greater expense) over monitoring CBC counts and LFT results.

Other adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis, and bone marrow depression. The most common reason for discontinuing the immune modifiers within the first few weeks is the development of abdominal pain; occasionally, a biochemically demonstrable pancreatitis occurs.

Concerns have been raised about the development of malignancy in patients taking azathioprine and 6-MP. Because the population that requires these medications is already at higher risk for the development of malignancy, the author believes that the available data on the use of azathioprine or 6-MP are insufficient and do not demonstrate a significant increase in the risk of malignancy.

An additional step III agent works by a different mechanism. Infliximab (Remicade) is an anti–TNF-alpha monoclonal antibody administered by infusion for the treatment of Crohn disease. Data supporting its use in persons with ulcerative colitis are not as convincing as the data for using it in persons with Crohn disease. Infliximab is administered as a single infusion of 5 mg/kg for the treatment of moderate-to-severe Crohn disease. For this indication, the response rate is 80% and the induction of remission rate is 50% after a single dose; with multiple dosing, higher rates of remission are attained.

Infliximab is also indicated for the treatment of fistulizing Crohn disease; for this indication, it is administered as 3 separate infusions of 5 mg/kg at weeks 0, 2, and 6, often followed by doses every 8 weeks. The fistula responds (closes) in 68% of patients treated with infliximab, although 12% develop an abscess. The duration of response is variable, lasting weeks to months; the duration of response can be increased with the concomitant use of immune modifiers. The response can be maintained by continuing regular dosing (ie, every 8 wk) after the induction dose. The response rate in persons with ulcerative colitis is not as good as in those with Crohn disease; from multiple small studies, the response rate in persons with ulcerative colitis is approximately 50%.

The adverse effects of infliximab commonly include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. Rare reports of lupuslike reactions and lymphoproliferative malignancies have been reported, although whether these are related to the drug remains uncertain.

Step IV (experimental treatments)

Generally, use these agents as part of an experimental protocol or in a setting in which the toxicities of the agents can be rapidly recognized and managed. Examples of some agents are provided, but a review of the literature is warranted before using them. In most cases, some subsets of patients respond; in general, large placebo-controlled trials have not yet established efficacy for these agents for the treatment of IBD.

Various experimental agents tend to be more disease-specific, ie, an agent works for Crohn disease but not ulcerative colitis, or vice versa. Experimental agents used in persons with Crohn disease include methotrexate (12.5-25 mg/wk orally or intramuscularly), thalidomide (50-300 mg/d orally), and interleukin 11 (1 mg/wk subcutaneously). Experimental agents used in persons with ulcerative colitis include cyclosporine A at a dose of 2-4 mg/kg/d intravenously (measure level; convert to oral dosing at 2-3 times the intravenous dose), nicotine patch (14-21 mg/d via topical patch), butyrate enema (100 mL per rectum twice daily), and heparin (10,000 U subcutaneously twice daily). Multiple contraindications, interactions, and precautions are associated with these drugs.

Symptomatic treatments

Because patients report symptoms (eg, diarrhea, spasm/pain, epigastric discomfort) and not inflammation per se, symptomatic relief is appropriate when indicated. This includes therapy with antidiarrheal agents, bile acid–binding agents, antispasmodics, and acid suppressants, as needed. These medications are not without complications, and caution is necessary.


Further Inpatient Care:
Day of admission

Admit the patient to the hospital if surgical intervention is anticipated or if he or she does not respond to outpatient treatment, is dehydrated, or has uncontrolled pain or diarrhea.

Start intravenous hydration. If indicated, obtain an abdominal flat plate image to exclude obstruction or megacolon. If the patient is nauseated or vomiting or has evidence of obstruction or megacolon, nasogastric intubation is indicated. Consider consultation with a surgeon.

If the patient has colitis, send a stool sample for C difficile toxin titer testing; also send one for routine culture and sensitivity testing if the patient has a new diagnosis of IBD. Laboratory studies to be considered include CBC count with differential, albumin level, ESR, glucose value, calcium level, magnesium level, phosphate value, electrolyte status, BUN/creatinine values, and a pregnancy test in females of childbearing age.

Initiate treatment with an oral aminosalicylate, intravenous corticosteroids, and metronidazole or ciprofloxacin (if antibiotics are indicated). Electrolyte correction and, potentially, transfusion, can be performed if indicated based on laboratory findings.

Keep patients NPO, except for medications (Crohn disease only); patients with ulcerative colitis may maintain a regular diet unless megacolon is present or surgery is being contemplated. Consider additional consultations with a registered dietitian and a stoma nurse if indicated. Consider line placement of central venous access.


Hospital day 1

If the abdominal flat plate findings were not diagnostic or if diagnostic concerns remain, order a barium study (small bowel series or barium enema). Although a colonoscopic evaluation also may be contemplated, consider the increased risk of perforation in persons with acute colitis.

Assess and correct the posthydration CBC count and electrolyte values, as indicated. Depending on the response to the initial interventions, advancement of the diet may be considered.


Hospital days 2 and 3

By the second hospital day, most patients should be showing clear evidence of clinical improvement. Assess the electrolyte status if intravenous fluids are still being administered. Consider advancement of the diet.

The corticosteroid dose can be tapered. If the patient is not improving, consider other treatment options; these may include hyperalimentation, other medical therapies, surgical intervention, or transfer to a tertiary care facility. Consider skipping to interventions typically enacted on day 3 or 4 (or discharge).

Hospital day 3 is similar to day 2. The corticosteroid dose can be reduced, and a switch to oral forms of all medications can be contemplated. If home treatments are needed (eg, home hyperalimentation), initiate arrangements for these. The diet can be advanced as tolerated. Consider skipping to day 4 or 5 interventions.


Hospital day 4

Continue to advance the diet, as tolerated. Continue the switch to oral medications. Many patients with a flare of Crohn disease or ulcerative colitis may be discharged by this time (occasionally even sooner); some may require another day of intravenous therapy.

If no progress has been made in the patient's condition since admission, additional treatments are necessary, including surgery or more aggressive medical treatments. Again, consider transfer to a tertiary care facility. If the patient has been unable to tolerate an oral diet, initiate hyperalimentation and/or reconsider surgical intervention.


Day of discharge/hospital day 5

Most patients should be able to be discharged on or before the fifth hospital day. A regular diet should be tolerated, with some restrictions if strictures are present. An ESR may be obtained to assist in future disease assessment but is unlikely to alter current management.

Discharge the patient on oral medications, with appropriate follow-up as an outpatient, typically within a few weeks.


Further Outpatient Care:
Outpatient medical care follows the approach outlined earlier in the article using the medications described .


Most outpatients' disease is in remission and requires little or no medication other than aminosalicylates (perhaps). Flares of IBD can generally be managed in an outpatient setting, primarily by stepping up the medication as described in the step-wise approach .


The biggest concern for outpatients is the duration and dosing of oral corticosteroids. This author uses a dose that is adequate to suppress inflammation (and thus symptoms), typically in the range of 20-40 mg of prednisone per day. Once symptoms are controlled, a rapid taper of the steroid follows. Patients in whom flares are frequent (>1-2 times/y), in whom the duration of steroid use is long (more than a few weeks each year), in whom reduction of the steroid dose causes recurrence of symptoms, or in whom steroids do not appear to be working are candidates for more intensive therapy. This higher step would include immune-modifying agents, infliximab, or experimental agents.


One health maintenance issue of particular importance to patients with IBD is a reduction in bone density, either from decreased calcium absorption (because of the underlying disease process) or because of corticosteroid use. Crippling osteoporosis can be a very serious complication for patients with IBD. The threshold for obtaining bone density studies should be low, and treatment (with bisphosphonates and calcium supplements) can be initiated in patients with significantly low bone density.


In/Out Patient Meds:
If a step-wise approach is observed, the least amount of medication that is effective can be used . Despite the widespread availability of home infusion, intravenous corticosteroids are still used only in hospital settings because of potential problems and the dosing schedule.


Home infusion of intravenous hyperalimentation is increasingly available for rare patients with Crohn disease in whom prolonged bowel rest is necessary. The short bowel may require prolonged hyperalimentation. Home intravenous antibiotics can also be arranged in this setting, if necessary.


Transfer:
The decision to transfer care of a patient (inpatient or outpatient) depends on the expertise and comfort level of the treating physician. Outpatient requests for a tertiary opinion should occur when patients have disease that is difficult to control with aminosalicylates and occasional brief courses of corticosteroids.


Relatively infrequent use and the monitoring necessary for azathioprine, 6-MP, and infliximab prompt some physicians to choose to refer patients to tertiary care centers when the need for these agents becomes apparent; others are comfortable handling these agents themselves.


For patients with refractory disease or those in whom corticosteroids cannot be weaned, referral for a second opinion generally is wise. Transfer inpatients for a tertiary opinion if the patient is not responding to intravenous steroids within a few days of admission; alternatively, strongly consider surgical intervention.


Deterrence/Prevention:
No known dietary or lifestyle changes prevent IBD.
Dietary manipulation may help symptoms in persons with ulcerative colitis, and it actually may help reduce inflammation in persons with Crohn disease .However, no evidence indicates that consuming or avoiding any particular food item causes or avoids flares of IBD.


Smoking cessation is the only lifestyle change that may benefit patients with Crohn disease. Smoking has been linked to increases in the number and severity of flares of Crohn disease. Smoking cessation is occasionally sufficient to achieve remission in a patient with refractory Crohn disease.


Complications:
See the subtopics in Clinical for the various complications that occur with IBD.


Prognosis:
Prognosis is discussed in Mortality/Morbidity. The typical course of IBD (for the vast majority of patients) includes periods of remission interspersed with occasional flares.


Ulcerative colitis

The average patient with ulcerative colitis has a 50% probability of having another flare during the next 2 years. However, the range of experiences is very broad; some patients may only have one flare over 25 years (as many as 10%), and others may have almost constant flares (much less common).


Patients with ulcerative colitis limited to the rectum and sigmoid at the time of diagnosis have a greater than 50% chance of progressing to more extensive disease and a 12% rate of colectomy over 25 years. More than 70% of patients presenting with proctitis alone continue to have disease limited to the rectum over 20 years. Most who develop more extensive disease do so within 5 years of diagnosis. Of patients with ulcerative colitis involving the entire colon, 60% eventually require colectomy, whereas very few of those with proctitis require colectomy. Of interest, most surgical interventions are required in the first year of disease; the annual colectomy rate after the first year is 1% for all patients.
Surgical resection for ulcerative colitis is considered curative for that disease, although postoperative pouchitis may occur in some patients. Of note, pouchitis is far more common in patients who have had a colectomy for ulcerative colitis than in those who have had a colectomy for other reasons (eg, familial adenomatous polyposis).


Crohn disease

The clinical course of Crohn disease is much more variable than that of ulcerative colitis. The clinical activity of Crohn disease is independent of the anatomic location and extent of disease. A patient in remission has a 42% likelihood of being free of relapse for 2 years and only a 12% likelihood of being free of relapse for 10 years. Over a 4-year period, approximately one quarter of patients remain in remission, one quarter have frequent flares, and one half have a course that fluctuates between periods of flares and remissions.
Surgery for Crohn disease is generally performed for complications (eg, stricture, stenosis, obstruction, fistula, bleeding) rather than for the inflammatory disease itself. After operation, the frequency of recurrence of Crohn disease is high, generally in a pattern mimicking the original disease pattern, often on one or both sides of the surgical anastomosis. Approximately one third of patients with Crohn disease who require surgery require surgery again within 5 years, and two thirds require surgery again within 15 years. Endoscopic evidence of recurrent inflammation is present in 93% of patients 1 year after surgery for Crohn disease. Surgery is an important treatment option for Crohn disease, but patients should be aware that it is not curative and that disease recurrence after surgery is the rule.


Patient Education:
Patients with IBD benefit tremendously from education about their disease. As a chronic, often life-long disease that is frequently diagnosed in young adulthood, increasing patient knowledge improves medical compliance and assists in the management of symptoms.
The Crohn's & Colitis Foundation of America (available at: www.ccfa.org) is the most prominent organization in the United States that can directly provide educational materials for patients. This organization also supplies physicians with educational brochures at no cost upon request.


For excellent patient education resources, visit eMedicine's Crohn Disease Center and Esophagus, Stomach, and Intestine Center. Medical/Legal Pitfalls:
Physicians may be at risk in certain areas of the treatment of patients with IBD. In general, these may be easily avoided by documenting appropriate education of the patient in the patient's medical record.


Patients with IBD are more prone to the development of malignancy. Persons with Crohn disease have a higher rate of small bowel malignancy. Because no effective screening protocol is available, this should not be an issue. Patients with pancolitis, particularly ulcerative colitis, are at a higher risk of developing colonic malignancy after 8-10 years of disease. The current standard of practice is to screen these patients with colonoscopy at 1- to 2-year intervals once they have had the disease for that duration. If a patient refuses appropriate screening, document it in the medical record.


Use of corticosteroids may lead to debilitating illness, particularly after long-term use. Warn patients who refuse to try more aggressive therapies and insist on continuing to take corticosteroids of the potential for long-term harm with these drugs, and take care to document these warnings and the alternatives offered in the medical record. Recommend to any patient who requires more than the rare short course of steroids that a yearly ophthalmologic examination is warranted because of the risk of cataract development.


Patients with IBD who are undergoing endoscopic procedures have higher complication rates than the general population; the informed consent obtained for endoscopic procedures should always mention bleeding and perforation as potential complications.

The single factor cited in most lawsuits involving endoscopy is failure to obtain adequate informed consent; missed malignancy and perforation are secondary.


Ulcerative colitis is a surgically curable disease. Keep this in mind in patients who are having significant difficulty with their disease or are having significant adverse effects from medications (particularly those related to long-term steroid use). This author makes certain to mention this (and document it) when first meeting any patient with ulcerative colitis.


If a decision is made to use or to continue immunosuppressant agents (ie, azathioprine, 6-MP) in a pregnant patient with IBD, the physician should be aware of the latest literature and should document the discussion of such with the patient, particularly given that these agents are still rated pregnancy class D by the Food and Drug Administration.


Special Concerns:
Because patients with IBD are often diagnosed in the peak of childbearing years, issues related to fertility, pregnancy, and childbearing are always a concern with the disease and its treatment.

Reproduction

In women, fertility is normal or only minimally impaired. Women considering pregnancy should not take immune modifiers (ie, 6-MP, azathioprine). Although some case reports and small series show no adverse outcomes of pregnancies in patients with IBD who are taking immune modifiers, birth defects are also reported. If a patient is taking an immune modifier and becomes pregnant, stopping the immune modifier and using steroids, as needed, is advisable in most instances. Vigilance for birth defects is appropriate.

For men with IBD, the major concern is the medications needed for treatment. Sulfasalazine can decrease sperm counts and sperm motility, causing a functional azoospermia; the other aminosalicylates do not seem to have this effect. The sperm effects are reversible by discontinuing the sulfasalazine. No firm evidence indicates that the use of immune modifiers in the father leads to more birth defects, although this has been suggested.


Pregnancy

Most infants are born healthy. The prevalence of prematurity, stillbirth, and birth defects is similar to that of the general population. The prevalence of spontaneous abortion is slightly higher in patients with IBD (12.2% vs 9.9% in the general population). Prior proctocolectomy or ileostomy is not an impediment to successful pregnancy.

In general, the aminosalicylates, including sulfasalazine, are safe during pregnancy. Folate supplements should be taken. Corticosteroids are also safe, but if high doses are needed near the end of the pregnancy, monitor the infant for signs of adrenal suppression. Current literature suggests that continuation of immune modifiers (ie, azathioprine, 6-MP) may be safe in pregnancy. Metronidazole (Flagyl) and ciprofloxacin (Cipro) are safe in pregnancy. The topical agents are generally safe in pregnancy.


Breastfeeding

Mothers who require medication to control of their IBD should strongly consider bottle feeding their infants. Sulfasalazine metabolites can be detected in breast milk; exercise caution. Low concentrations of mesalamine and higher concentrations of its metabolites can be detected in breast milk. The significance of this is unknown. Corticosteroids can also be detected in breast milk. Immune modifiers are excreted in breast milk; either the immune modifier should be discontinued or the infant should be bottle fed. Metronidazole (Flagyl) and ciprofloxacin (Cipro) are excreted in breast milk; discontinue nursing or discontinue the drugs.

Although small amounts of the topical agents are absorbed, and thus may be excreted in breast milk, the concentrations are much lower than with the oral forms of the same medications. These medications are probably reasonably safe in breastfeeding.


Medications, safety in pregnancy

All of the aminosalicylates and the corticosteroids appear to be safe in women in all phases of fertility, pregnancy, and lactation. Men should avoid sulfasalazine (Azulfidine) during periods when they and their mates are attempting to become pregnant.

The antibiotics (ie, metronidazole, ciprofloxacin) should generally be avoided during lactation; they are probably safe for fertility and during pregnancy.

The immune-modifying agents (ie, 6-MP, azathioprine) should be considered only on a case-by-case basis.


Aspirin and nonsteroidal anti-inflammatory agents in IBD

Currently, substantial controversy has been raised in the medical/IBD community regarding the effects of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) on IBD. Published data and recommendations indicate that aspirin and NSAIDs cause a number of flares of IBD and, thus, should be avoided in all patients with IBD. On the other hand, studies also indicate that only a very minor link exists between the use of aspirin or NSAIDs and flares of IBD.

This author's practice is to administer aspirin or NSAIDs judiciously when indicated (eg, with arthritis and/or arthralgias associated with IBD), with the caveat that the patient is warned of the possibility that the medication may cause a flare of the IBD. If, shortly after starting the NSAID, a flare occurs, then the NSAID should be discontinued. If the patient's disease remains in remission, the patient can be maintained on the NSAID as necessary.




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INFLAMMATORY BOWEL DISEASE
BREAKTHROUGHS IN THE MANAGEMENT OF INFLAMMATORY BOWEL DISEASE
N H Banka
Consultant Gastroenterologist and Hepatologist, Bombay Hospital and Medical Research Centre, Formerly, Consultant gastroenterologist at Sir JJ Group of hospitals and Grant Medical College, Sir Hurkisondas Hospital and Nanavati Hospital.
Breakthroughs in newly developed agents have included not only new compounds and modes of delivery, but also entirely novel therapeutic modalities.

Biologic therapies have begun to assume prominent role. Clinical observations, pilot studies and extrapolation of results from other Immuno-inflammatory diseases (Rheumatoid arthritis), provide important insights into mechanism of risk benefit, action and sample size estimates for the design and implementation of controlled trials. This is true for inflammatory bowel disease (IBD) where a constant flow of breakthroughs are reaching the professional and layman journals. However, even with the advent of regulatory approval of new treatments, such as Infliximab, the evidence base may be insufficient to predict the eventual optimisation of treatment strategies until years after the agents availability in the market.

Aminosalicylates
The only "new" aminosalicylate is Balsalazide, which is a pro-drug. In recent trials this molecule has comparable efficacy and safety to mesalamine in the induction and maintenance of remission for ulcerative colitis.

Corticosteroids
Budesonide is marketed in different countries for the treatment of IBD. Potential therapeutic advantage over systemic steroids include a) an increased binding potency for the glucocoticoid receptor and b) increased "first-pass" hepatic metabolism. This drug can also be used to reach specific sites in the form of targeted delivery. The therapeutic efficacy has been similar to other steroids without inhibition of the hypothalamus-pituitary-adrenal axis.

Budesonide enemas are not as efficacious as topical mesalamine.

Immunomodulators
Niether azathioprine nor mercaptopurine is considered a new therapy for IBD. Important and practical aspects of their usage remains to be defined in ulcerative colitis (UC) and Crohn's disease (CD). It could prove to be efficacious drug with initial steroid therapy and concurrent treatment with aminosalicylates.

A recent, small trial has suggested that intravenous cyclosporin without steroids may be efficacious for acute UC. Long term immunomodulation is beneficial after acute cyclosporin therapy with azathioprine. Other oral agents such as tacrolimus also have been evaluated in preliminary trials of UC and CD but controlled data is lacking.

Mycophenolate has also been studied but requires additional studies of safety and efficacy before it can be considered a standard approach.

Biologics
The introduction of infliximab into the US marketplace has been the first real advance for the treatment of IBD since the general acceptance of immunomodulation. Three controlled trials have set the expectations for these new therapies andpredict the eventual utility of infliximab. There was excellent efficacy for refractory disease but a gradual decline in efficacy over the ensuing 12 month period, particularly in patients who did not receive re-treatment. Similar results were obtained in fistulising CD.

Tight on the heals of infliximab are other anti-TNF strategies as an humanised version of a monoclonal anti-TNF (CDP571) and the potential use of eternacept, humanised soluble receptors for TNF. Most recently, thalidomide has also been explored in early trials for CD with optimistic reports of efficacy.

Molecular engineered formulations of human recombinant interleukin-10 and interleukin-11 have entered clinical trials in IBD as have anti-sense compounds targeting inhibition of adhesion molecules (ICAM-1). It is anticipated that monoclonal antibody and anti-sense technologies will continue to assess specific mediators such as NF kappa, gamma-interferon and interleukin-12. Evolving methods of influencing cytokine production and regulation, including the use of viral vectors are presently on the horizon.

Nicotine
The protective role of cigarette smoking against the development of UC has led to trials utilising nicotine as adjunctive therapy. A series of trials using nicotine patches has supported a role for nicotine therapy in the symptomatic management of UC. At present nicotine should not be used as a proven therapy for UC but may be considered in the patients whose UC aggravated after smoking cessation.

Short Chain Fatty Acids
Short chain fatty acids enhance the colonocyte-nutrient oxidation, thus improving the ongoing colonocyte dysfunction. It has been used as mixed SCFD or butyrate as enematas in distal UC. While in most studies there was a positive benefit, the overall response rate is not substantially different from placebo. At the present time this mode of therapy cannot be advocated for the routine management of UC.

Fish Oil, Omega-3 fatty Acids and Leukotriene Inhibitors
Trials involving omega-3 fatty acids were performed in the early and mid-1990s for refractory UC or as maintenance therapy. In these trials the clinical benefit was modest, at best, and these therapies have not been accepted within the current practice guidelines for UC. The development of an enteric coated fish oil preparation, recently effective in a Crohn's disease maintenance trial, may eventually offer an alternative therapeutic option in IBD.

The potential role of inhibition of 5-lipoxygenase and leukotriene B4 led to development of specific 5-lipoxygenase inhibitors. However, in contrast to asthma, specific inhibition of a distal mediator of inflammation has failed to provide adequate therapy for either active UC or prevention of relapse.

Heparin
Observations regarding a "paradoxical" improvement in colitis with heparin therapy and improvement in extraintestinal manifestations of IBD have led to the possibility that heparin may have a therapeutic role in IBD. While heparin does appear to be safe in the setting of UC it remains to be determined where heparin therapy will fall in the armamentarium for IBD and whether the new developments in low molecular weight heparin will provide similar therapeutic potential.

Probiotics
An intriguing area of therapy has been the potential for probiotic therapy for IBD. Recent european trials have begun to suggest efficacy for probiotic therapy for UC and CD. We anxiouslyawait further evidence for this expanding alternative approach.

Challenges in the field of IBD is not only identifying the novel agents, but also defining the end points and identifying the efficacy at the biologic level. Clinicians are only just beginning to recognize subclinical markers of response. Looking back at successes and failures in newer breakthroughs to treating IBD, it may be tempting, although extremely difficult to draw conclusions about pathogenesis. Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is simple binding and clearing or deletion of the activated macrophage. Thus, when a therapy proves effective, do clinicians truly know how it works? In this context it is the write time to remember Sir William Osler's saying -"I always use the newest medicine first, Before its effectiveness wears off".


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IBD FAQ's
Inflammatory Bowel Disease
What Causes IBD?
How Do I Know if I Have Ulcerative Colitis?
Does Ulcerative Colitis Increase the Risk of Colon Cancer?
How Do I Know if I Have Crohn’s Disease?
What are the Complications Associated with Crohn ’s Disease?
What is the Treatment for IBD?
Should I Modify or Change My Diet?
How Do I Cope with IBD?
When is Surgery Needed?
Glossary
Additional Reading


Digestion of food begins in the mouth and moves through the esophagus, stomach, and the small and large intestine. In the mouth, stomach, and the small intestine, food is mixed with digestive juices. The digestive juices break the food down into smaller chemical pieces or nutrients. These nutrients move along the small intestine, which is made up of three parts: the duodenum, jejunum, and ileum. The nutrients are absorbed into the bloodstream through the small intestine and carried to all parts of the body. Nutrients are needed for the body to grow and remain healthy.

The water and solid waste that remain after the nutrients are absorbed move into the large intestine. Most of the remaining water is absorbed into the bloodstream from the colon. The solid waste is passed out of the body as a bowel movement (BM) through the anus.

Inflammatory Bowel Disease (IBD) is a term that refers to both ulcerative colitis and Crohn’s disease. Ulcerative colitis causes inflammation of the lining of the large intestine. Crohn’s disease causes inflammation of the lining and wall of the large and/or small intestine. When inflamed, the lining of the intestinal wall is red and swollen, becomes ulcerated, and bleeds.

What Causes IBD?
The cause(s) of IBD are not known, but there are several theories. One theory is based on genetics indicating that IBD does run in families. About 15 percent to 30 percent of patients with IBD have a relative with the disease. There is research going on to find out if a specific gene or a group of genes makes a person more susceptible to getting the disease.

Many changes in the body’s immune system (body’s natural defense system against disease) have been discovered in patients with IBD. What is still unknown is what causes those changes to happen. There is a large amount of research being done in this area.

There is little evidence that stress causes IBD. As with other illnesses, stress may aggravate symptoms and require a treatment program.

IBD occurs most frequently in people in their late teens and twenties. There have been cases in children as young as two years old and in older adults in their seventies and eighties. Men and women have an equal chance of getting the disease.

Ulcerative Colitis
Most often ulcerative colitis occurs in young people 15 to 40 years of age. Ulcerative colitis occurs only in the inner lining of the colon (large intestine) or rectum. When it is located only in the rectum, it is called proctitis. Inflammation of the rectum and colon keeps water from being absorbed into the bloodstream and results in diarrhea.

Symptoms of Ulcerative Colitis
The most common symptoms of ulcerative colitis are diarrhea, abdominal cramps, and rectal bleeding. Some people may be very tired and have weight loss, loss of appetite, abdominal pain, and loss of body fluids and nutrients. Bleeding may be serious, leading to anemia (low red blood cell count). Joint pain, redness and swelling of the eyes, and liver problems can also occur. No one knows for sure why problems outside the colon are linked with colitis. These problems may improve when the colitis is managed.

Ulcerative colitis is an illness that has periods of remission (time when you feel well) and relapse (time when you feel ill). Half of the people who have ulcerative colitis have only mild symptoms. Others have frequent fever, bloody diarrhea, nausea, and severe abdominal cramps.

Some people with severe symptoms of ulcerative colitis must go to the hospital to correct malnutrition and stop diarrhea and loss of blood. In the hospital, a patient may need a treatment program including a special diet and feeding through a vein. Sometimes surgery is needed.

How Do I Know if I Have Ulcerative Colitis?
To find out if you have ulcerative colitis, your doctor must take your medical history and perform a physical examination. The exam may include blood tests and samples of a bowel movement. Other tests include:

Flexible Sigmoidoscopy or Colonoscopy - A small flexible tube inserted by your doctor into the anus. The flexible tube is slowly passed into the lower third of the colon in flexible sigmoidoscopy and through the entire colon in a colonoscopy, allowing your doctor to see the lining of the colon. If necessary, the doctor can take a tissue sample called a biopsy to make a diagnosis of your condition.

Barium Enema---This is an X-ray of the colon. A white substance called barium is put into the colon by an enema. This test may allow your doctor to see areas of the colon that are abnormal.

Does Ulcerative Colitis Increase the Risk of Colon Cancer?
Risk of colon cancer is higher in ulcerative colitis patients with involvement of the entire colon and in patients who have had the diagnosis for eight to ten years. Patients with a diagnosis of left-sided ulcerative colitis for 15-20 years also fall into a higher risk group for developing cancer. Individuals in these groups should consult their doctor and plan for periodic colonoscopy with biopsy.

Crohn’s Disease
Crohn’s is a chronic disease that has periods of remission (time when person feels well) and relapse (when a person feels ill).

Crohn’s disease is an inflammation and ulceration process that occurs in the deep layers of the intestinal wall. The most common areas affected are the lower part of the small intestine, called the ileum, and the first part of the colon. This type of Crohn’s disease is called ileocolitis.

Crohn’s disease can infrequently affect any part of the upper gastrointestinal tract. Aphthous ulcers, which are similar to cold sores, are common. Ulcers can also occur in the esophagus, stomach, and upper small intestine (duodenum). It is difficult to tell these ulcers from peptic ulcers except by biopsy exam.

Symptoms of Crohn’s Disease
The most common symptoms of Crohn’s disease are pain in the abdomen, often in the lower right side, diarrhea, and weight loss. There may also be rectal bleeding and fever. Chronic bleeding may lead to a low red blood cell count called anemia. Children who develop Crohn’s disease may have delayed development and stunted growth.

How Do I Know if I Have Crohn’s Disease?
To find out if you have Crohn’s disease, your doctor must take your medical history and do a physical exam. The exam may include blood tests and samples of a bowel movement. Other tests are the same as described in the section on Ulcerative Colitis; a barium enema and a colonoscopy examination. In addition, a small bowel X-ray may be required.

What are the Complications Associated with Crohn’s Disease?
The most common complication of Crohn’s disease is blockage of the intestine. Blockage or stricture occurs when the disease thickens the bowel wall with swelling and scar tissue. The intestine passage becomes smaller and smaller, until it is completely closed.

Fistulas are a common complication of this disease. Fistulas occur when ulcers in the intestine break through the intestine wall making tunnels into surrounding tissues of the bladder, vagina, or into the skin. Fistulas occur frequently around the anus and rectum.

These fistulas can become infected and may result in abscess formation. Treatment programs are used to manage infected fistulas, but often surgery is needed.

What is the Treatment for IBD?
Your doctor will discuss with you a treatment plan that may include any of the following:

Nutrition
Emotional Support
Surgery
Drug Therapy
There are many different types of treatment plans that your doctor can prescribe to control the symptoms of IBD, and each of these has specific actions and side effects. Be sure to follow all of your doctor’s directions. Never stop your treatment plan until you have completed it or your doctor instructs you to stop.

Should I Modify or Change My Diet?
What you eat does not cause IBD, but can cause symptoms when the disease is active.

The goal of nutritional management for people with IBD is to modify the diet to decrease gastrointestinal (GI) symptoms while maintaining adequate nutrient intake. Your doctor may do a nutritional assessment to determine if you are taking in enough calories, vitamins, and minerals. When nutritional needs are not being met, your doctor may suggest a liquid supplement.

How Do I Cope with IBD?
Although IBD is a chronic disease that has periods of remission and relapse, most people have a normal life span and a good quality of life.

For those who have chronic and continuing symptoms, the following apply:

Know your body and how IBD affects you
Learn to care for yourself, have control over those things you can control
Develop a support system that works for you: family, friends, and support groups
Be sure to follow instructions from your medical team


When is Surgery Needed?
Most people who have IBD respond to their treatment program, including medications and nutritional planning. Many patients have mild episodes of illness after long periods of feeling well. Your doctor will consider surgery usually when certain conditions are present. Surgery may be needed if there is:

A large amount of bleeding
Long-lasting and serious illness
Ulceration that makes a hole in the intestinal wall
Medical treatment plan is not controlling the disease
Obstruction
There are several surgical choices. Each has advantages and disadvantages. The surgeon and patient must decide on the best option.

Staying informed is an important aspect of dealing with IBD.

Glossary
Absorption - the process of nutrients passing from the intestine into the blood stream.

Anemia - a condition in which the blood does not have enough red blood cells.

Anus - opening at the end of the rectum that allows solid waste to be eliminated.

Aphthous Ulcers - a sore on the mouth that is associated with CrohnÕs disease.

Chronic Disease - illness that occurs at frequent intervals over a long period of time.

Colon - the large intestine.

Chrohn’s Disease - an inflammatory and ulcerative process that occurs in the deep layers of the small and sometimes large intestine.

Digestion - the process of breaking down food into its simplest chemical compounds so that it can be absorbed.

Duodenum - the first portion of the small intestine. Connects the stomach to the small intestine.

Fistulas - an abnormal passage leading from the colon to other organs in the lower abdominal cavity.

Ileocolitis - a common form of Crohn’s disease that affects the lower portion of the small intestine and the first portion of the colon called the ileum.

Ileum - the last portion of the small intestine that connects to the large intestine.

Immune System - the body’s natural defense system that fights against disease.

Inflammation - a response to tissue injury that causes redness, swelling, and pain.

Jejunum - the middle portion of the small intestine.

Large Intestine - also known as the colon. Primary function is to absorb water and get rid of solid waste.

Malnutrition - condition that occurs when the body does not have enough calories, vitamins, and minerals to maintain growth and health.

Proctitis - inflammation of the rectum.

Rectum - lowest portion of the colon.

Small Intestine - Connects to the stomach and large intestine. Absorbs nutrients.

Stricture - closure or obstruction of the intestine.



SOURCE:
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