Drug-induced colitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qasim Salau, M.B.B.S., FMCPaed [2]

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

Historical Perspective

• [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
• In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
• In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].

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:

Pathophysiologic pattern of colitis	Drugs
Focal active colitis	NSAIDs, sodium phosphate (oral)
Eosinophilic colitis	NSAIDs, carbamazepine, antiplatelet drugs, estrogen, progesteron, gold
Ischemic colitis	NSAIDs, digoxin, diuretics, cocaine, ergotamine, serotonin agonists/antagonists, amphetamines, glutaraldehyde, antibiotics, chemotherapy drugs, drugs that cause constipation, laxatives, vasopressor agents, estrogen, progesteron, mycophenolic acid
Microscopic colitis	NSAIDs, Protein pump inhibitors (lansoprazole), H2 receptor blockers (e.g. ranitidine), ticlopidine, simvastatin, carbamazepine, sertraline, oral penicillin
Pseudomembranous colitis	Antibiotic-associated Clostridium difficile colitis (e.g. penicillins, clindamycin, cephalosporins, fluoroquinolones)
Apoptotic colitis	NSAIDs, oral sodium phosphate, laxatives, chemotherapy drugs (especially anti-metabolites), and cyclosporine A
Neutropenic necrotizing enterocolitis	Chemotherapy drugs
Immune-mediated colitis	Antibody to cytotoxic T-lymphocyte–associated antigen (CTLA4)

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.

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. Submucosal fibrosis with destruction of normal mucosal architecture is seen in diaphragm disease.

• 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:

Pathophysiologic pattern of colitis	Drugs
Focal active colitis	NSAIDs, sodium phosphate (oral)
Eosinophilic colitis	NSAIDs, carbamazepine, antiplatelet drugs, estrogen, progesteron, gold
Ischemic colitis	NSAIDs, digoxin, diuretics, cocaine, ergotamine, serotonin agonists/antagonists, amphetamines, glutaraldehyde, antibiotics, chemotherapy drugs, drugs that cause constipation, laxatives, vasopressor agents, estrogen, progesteron, mycophenolic acid
Microscopic colitis	NSAIDs, Protein pump inhibitors (lansoprazole), H2 receptor blockers (e.g. ranitidine), ticlopidine, simvastatin, carbamazepine, sertraline, oral penicillin
Pseudomembranous colitis	Antibiotic-associated Clostridium difficile colitis (e.g. penicillins, clindamycin, cephalosporins, fluoroquinolones)
Apoptotic colitis	NSAIDs, oral sodium phosphate, laxatives, chemotherapy drugs (especially anti-metabolites), and cyclosporine A
Neutropenic necrotizing enterocolitis	Chemotherapy drugs
Immune-mediated colitis	Antibody to cytotoxic T-lymphocyte–associated antigen (CTLA4)

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 table below lists the differential diagnosis of common causes of colitis:

Diseases	History and Symptoms				Physical Examination				Laboratory findings				Other Findings
	Diarrhea	Rectal bleeding	Abdominal pain	Atopy	Dehydration	Fever	Hypotension	Malnutrition	Blood in stool (frank or occult)	Microorganism in stool	Pseudomembranes on endoscopy	Lab Test 4
Allergic Colitis	+	++	+	++					++
Chemical colitis	+	++	++		+	+		+			+
Infectious colitis	++	++	+		+++	+++	++		+	++	+
Radiation colitis	+	++	+		+			+
Ischemic 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. Most reports of drug-induced colitis have been related to NSAIDs 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 drug-induced colitis does not vary by gender.

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 not fully defined. The symptoms often develop insidiously in the majority of patients and may require hospitalization in about 20% of them. Early symptoms include abdominal pain, diarrhea and intestinal bleeding. In majority, the symptoms resolve following stoppage of the offending NSAID and symptomatic treatment. Long-term NSAID may result in development of intestinal strictures.

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
• Intestinal obstruction from diaphragm-like lesions
• Failure to thrive

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].