Drug-induced colitis
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Synonyms and keywords: Drug-related colitis, Drug-induced enterocolitis, Non-steroidal anti-inflammatory drug (NSAID) induced colitis; Chemotherapeutic drug-induced colitis

# Overview
Drug-induced colitis is inflammation of the large intestine or colon, caused by the introduction of drugs or chemicals to the colon usually by the oral route but occasionally through the rectum. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common drugs implicated in drug-induced colitis and also the most commonly used drugs worldwide. Drug-induced colitis can resemble ulcerative colitis, infectious colitis and ischemic colitis endoscopically. Most cases of drug-induced colitis resolve after stopping the offending medication.

# Historical Perspective
- NSAID-induced colitis was first described by Debenham, a Canadian doctor, in 1966 following a patient who developed ulcer in the caecum during oxyphenbutazone therapy.
- Diaphragm disease was first mentioned in 1987, by Lang et al to describe small bowel strictures from NSAIDs use.
- Sheers and Williams in 1989, subsequently described similar diaphragm disease in the colon of patients on NSAIDs.

# Classification
- There is no established classification method for drug-induced colitis. However, it may be classified based on the pathophysiology pattern, type of drug and duration of symptoms.

## Classification based on histologic pattern
Based on the pathophysiology, drug-induced colitis may be classified into:

## Classification based on type of drugs
Drug-induced colitis can be classified based on the type of drugs into:
- Non-steroidal anti-inflammatory drugs (NSAID)-induced colitis
- Chemotherapy drug-induced colitis
- Antibiotic-associated Clostridium difficile colitis
- H2 receptor blockers induced colitis

## Classification based on duration of symptoms
Based on the duration of symptoms, drug-induced colitis can be classified into:
- Acute
- Chronic e.g. diaphragm disease (results from long-term use of NSAIDs)

# Pathophysiology

## Pathogenesis
- The pathogenesis of drug-induced colitis depends on the causative drug. The most common drugs implicated in drug-induced colitis are NSAIDs.
The exact mechanism by which NSAID cause colitis is not completely understood. NSAIDs can either induce new-onset colitis or exacerbate a pre-existing colitis.
NSAIDs inhibit cyclooxygenase and thus prostaglandin production. Prostaglandin helps to maintain mucosal integrity. NSAIDs also impair oxidative phosphorylation, increasing risk of oxidative injury to the gut.
Direct damage to the intestinal mucosa is another proposed mechanism in NSAID related injury, since the rectum is often spared with colitis mainly limited to the right side of the colon.
Increased intestinal permeability to antigens following the use of NSAIDs is another hypothesized mechanism. This is said to cause the activation of the immune system and subsequent inflammation.
- The exact mechanism by which NSAID cause colitis is not completely understood. NSAIDs can either induce new-onset colitis or exacerbate a pre-existing colitis.
NSAIDs inhibit cyclooxygenase and thus prostaglandin production. Prostaglandin helps to maintain mucosal integrity. NSAIDs also impair oxidative phosphorylation, increasing risk of oxidative injury to the gut.
Direct damage to the intestinal mucosa is another proposed mechanism in NSAID related injury, since the rectum is often spared with colitis mainly limited to the right side of the colon.
Increased intestinal permeability to antigens following the use of NSAIDs is another hypothesized mechanism. This is said to cause the activation of the immune system and subsequent inflammation.
- NSAIDs inhibit cyclooxygenase and thus prostaglandin production. Prostaglandin helps to maintain mucosal integrity. NSAIDs also impair oxidative phosphorylation, increasing risk of oxidative injury to the gut.
- Direct damage to the intestinal mucosa is another proposed mechanism in NSAID related injury, since the rectum is often spared with colitis mainly limited to the right side of the colon.
- Increased intestinal permeability to antigens following the use of NSAIDs is another hypothesized mechanism. This is said to cause the activation of the immune system and subsequent inflammation.

## Genetics
- There is no specific genetic cause for drug-induced colitis

## Gross Pathology
Gross pathology findings in drug-induced colitis depends on the causative drug.
- NSAID-induced colitis is characterized by nonspecific mucosal erosions and ulcers of varying degree, with intervening areas of normal mucosa. Perforations and fibrosis may also be seen. The lesions are predominantly on the right and may be single or multiple, sparing the rectum.
- Pseudomembranes may be seen in NSAID-induced colitis and antibiotic induced Clostridium difficile colitis.

## Microscopic Histopathology
- On histology, NSAID-induced colitis findings include ulcers that are often discrete and superficial with minimal inflammatory cells which are mainly eosinophils and lymphocytes. The area of pathology is surrounded by normal colonic mucosa. In diaphragm disease, characteristic submucosal fibrosis (the fibers pointing in the direction of peristalsis) with submucosal architectural destruction and normal or minimal inflammation of the overlying epithelium is seen. 
- Other histologic findings associated with drug-induced colitis include increased epithelial apoptosis especially involvement of the crypts, presence of pseudomembranes, cytoplasmic vacuoles,  and features of microscopic colitis (presence of subepithelial thickening and/ or increased lymphocytes within the crypts in an otherwise normal looking mucosa).

# Causes
- The most common causes of drug-induced colitis are NSAIDs.
Causes of drug-induced colitis include:

# Differentiating drug-induced colitis from other Diseases
- Drug-induced colitis must be differentiated from other diseases that cause diarrhea especially bloody diarrhea and abdominal pain. The symptoms of drug-induced colitis may overlap with other forms of colitis such as inflammatory bowel disease and ischemic colitis.
- The symptoms of colitis such as diarrhea especially bloody diarrhea and abdominal pain are seen are seen in all forms of colitis. The table below lists the differential diagnosis of common causes of colitis:

# Epidemiology and Demographics
The overall prevalence and incidence of drug-induced colitis is not known.

## Epidemiology
- The overall prevalence and incidence of drug-induced colitis is not known. NSAIDs are the most common prescribed drugs worldwide and most reports of drug-induced colitis have been related to their use.
- The incidence of NSAID-induced colitis is reported as 10 percent of all cases of colitis.

## Demography

### Age
NSAID-induced colitis is more common among the elderly. This may be related to the increased use of NSAIDs in this age group.

### Gender
The prevalence and incidence of NSAID-induced colitis is more in women than men. 

### Race
There is no racial predilection to drug-induced colitis

# Risk Factors
- Common risk factors in the development of NSAID-induced colitis include: 
- Elderly age group
- Long-term NSAID use
- Alcohol use
- Smoking

# Natural History, Complications and Prognosis

## Natural History
- The severity and extent of drug-induced colitis depend on the offending drug and duration of use the drug.
- The natural history of NSAID-induced colitis is poorly defined. In the majority of patients the symptoms often develop insidiously following months of use of NSAIDs and may require hospitalization in about 20% of them. Early symptoms include abdominal pain, diarrhea and intestinal bleeding. There symptoms usually resolve following stoppage of the offending NSAID and symptomatic treatment. Long-term NSAID use may result in development of intestinal diaphragm strictures which persist.

## Complications
Complications of NSAID-induced colitis include:
- Perforation
- Peritonitis
- Diaphragm-like strictures
- Iron deficiency anemia

## Prognosis
The prognosis of drug-induced colitis varies with the offending drug. It is generally good with resolution of symptoms following treatment.

# Diagnosis

## Diagnostic Criteria
- There is no definitive diagnostic criteria for drug-induced colitis. Diagnosis of drug-induced colitis is primarily clinical, based on detailed history, physical examination and endoscopic findings.

## Symptoms
- Obtaining a complete history including drug history is important in making a diagnosis of drug-induced colitis. Symptoms of drug-induced colitis are not specific,
- Symptoms of NSAID-induced may include the following:
- Diffuse abdominal pain which is colicky
- Diarrhea
- Rectal bleeding
- Vomiting
- Chronic symptoms include:
- Symptoms of iron-deficiency anemia
- Recurring episodes of constipation due to partial intestinal obstruction in patients with diaphragm disease
- Failure to thrive

## Physical Examination
- Physical examination findings in patients with NSAID-induced colitis may be remarkable for:
- Abdominal tenderness  which is often diffuse
- Pallor due to anemia
- Signs of dehydration such as lethargy, Tachycardia and Hypotension
- Fever due to dehydration or in individuals who have developed sepsis
- Toxic appearance in those with bowel perforation and sepsis
- Weight loss in patients with diaphragm disease

## Laboratory Findings
There are no specific laboratory findings associated with chemical colitis. Initial investigations should include hematological, biochemistry profiles and stool examination.

### Hematology
- Anemia

### Electolytes
- Hyponatremia

### Stool Examination
Stool analysis may show
- Fecal occult blood
- Stool culture is negative.

## Endoscopy
- Endoscopy is required for diagnosis of drug-induced colitis.
- Endoscopic features in NSAID-induced colitis include:
- Normal mucosal which may be seen in as much as 45% of the patients.
- Nonspecific mucosa changes such as friable, hyperemic, edematous mucosa with/ or without erosions and ulcers. This findings may be seen in any part of the colon, but more commonly on the right side.
- In diaphragm disease, multiple diaphragm-like membrane strictures are seen with normal or minimally inflamed surrounding mucosa.

## Other Diagnostic Studies
- Other diagnostic test include

### CT scan
There is no specific CT scan feature for NSAID-induced colitis.

### Xray
There is no specific Xray feature of NSAID-induced colitis. However, it may help to rule out complications such as intestinal obstruction and perforation.

# Treatment

## Medical Therapy
- There is no specific treatment for NSAID-induced colitis; the mainstay of therapy is medical supportive care.
- Medical treatment include:
- Stoppage of use the offending NSAID
- Correction of anemia
- Correction of dehydration and electrolyte derangements by giving intravenous fluids or oral rehydration therapy whenever it is feasible
- Broad-spectrum antibiotic given as an adjunct therapy

## Surgical Therapy
Surgical intervention may occasionally be required in NSAID-induced colitis. It is usually reserved for management of complications such as bowel perforation and stenosis. Surgical treatment include endoscopic dilatation, open dilatation or bowel resection. 

## Prevention
- There are no established preventive measures available for NSAID-induced colitis.