Colitis Differential Diagnosis: A Comprehensive Guide for Clinicians

Colitis, characterized by the inflammation of the colon’s mucosal lining, is an increasingly prevalent condition encountered in clinical practice. Patients suffering from colitis may exhibit a range of symptoms, including watery diarrhea, abdominal discomfort, tenesmus, urgency to defecate, fever, generalized fatigue, and the presence of blood in their stool. The etiology of colitis is diverse, encompassing infectious agents, autoimmune disorders, ischemic events, exposure to toxins, immunodeficiency states, and radiation injury. This article aims to provide a comprehensive overview of the evaluation and management of colitis, emphasizing the crucial role of differential diagnosis in guiding appropriate clinical strategies and the collaborative approach of an interprofessional team in optimizing patient care. Effective management of colitis necessitates a thorough understanding of its multifaceted nature, and this review will delve into the etiology, epidemiology, pathophysiology, evaluation, management, and potential complications of colitis, ultimately highlighting the significance of interprofessional collaboration in enhancing healthcare outcomes.

Etiology of Colitis

In adult patients, colitis can arise from a variety of causes. A systematic approach to Colitis Differential Diagnosis requires consideration of the following etiologies:

1. Infections: A broad spectrum of infectious agents can induce colitis. Bacterial culprits include Campylobacter jejuni, Escherichia coli, Salmonella, Shigella, Mycobacterium tuberculosis, and Clostridium difficile, the latter being responsible for pseudomembranous colitis. Parasitic infections, such as Entamoeba histolytica, and viral infections, notably cytomegalovirus (CMV), are also recognized causes.
2. Inflammatory Bowel Disease (IBD): IBD encompasses Crohn’s disease (CD) and ulcerative colitis (UC), both chronic inflammatory conditions of the gastrointestinal tract. Differentiating between UC and CD is a key aspect of colitis differential diagnosis.
3. Microscopic Colitis: This condition is a relatively common cause of persistent watery diarrhea, particularly in elderly individuals. Microscopic colitis is further categorized into collagenous colitis (CC) and lymphocytic colitis (LC). These subtypes share clinical similarities, with the primary distinction being the presence of a thickened subepithelial collagen band in collagenous colitis. Microscopic colitis has known associations with autoimmune disorders like celiac disease, type 1 diabetes, thyroid dysfunction, and psoriasis.
4. Ischemic Colitis: Ischemic colitis develops when the colonic blood supply is insufficient to meet the metabolic demands of the colon. This hypoperfusion leads to mucosal ulceration, inflammation, and hemorrhage. Identifying risk factors for ischemia is crucial in the colitis differential diagnosis.
5. Drug-Induced Colitis: Certain medications can trigger colitis as a side effect. These include non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, proton pump inhibitors (PPIs), H2 receptor antagonists, beta-blockers, statins, immunosuppressive drugs, and vasopressors. A thorough medication history is essential in the colitis differential diagnosis.
6. Colitis Secondary to Immune Deficiency Disorders: Conditions causing immune deficiency can predispose individuals to colitis.
7. Tuberculous Colitis: Colitis caused by Mycobacterium tuberculosis.
8. Radiation Colitis: Pelvic radiotherapy, often used for gynecological, urological, and rectal cancers, can result in radiation-induced colitis.

Epidemiology of Colitis

Understanding the epidemiology of different types of colitis is valuable in formulating a colitis differential diagnosis.

Campylobacter jejuni stands out as the most frequent bacterial cause of diarrheal illness globally, with an estimated prevalence of 25 to 30 cases per 100,000 individuals. Salmonella and Shigella infections are also significant, with prevalence estimates around 20 cases per 100,000 population.

Inflammatory bowel disease (IBD) is demonstrating an increasing trend in incidence and prevalence across various regions worldwide, with North America and Europe reporting the highest rates. In the United States, the prevalence of IBD in adults is approximately 263 per 100,000.

Microscopic colitis predominantly affects older adults, with an average age of onset between 50 and 70 years. It is more commonly diagnosed in women than men, with the female-to-male ratio being notably higher in collagenous colitis, reaching up to 9:1. The incidence of microscopic colitis ranges from 1 to 30 per 100,000 person-years.

The incidence of ischemic colitis has shown a significant increase over the past decades, rising from 6.1 cases per 100,000 person-years in the period 1976-1980 to 22.9 per 100,000 in 2005-2009. This increase may be attributed to factors such as advancements in medical interventions and the wider use of endoscopy for diagnosis, as well as the aging population and increased prevalence of comorbidities.

Mycobacterium tuberculosis colitis is endemic in many parts of the world, and a resurgence of tuberculosis has been observed in Western countries. The global annual incidence of tuberculosis is estimated at 9.4 million cases. The global case fatality rate for tuberculosis ranges from 23% to 25%, exceeding 50% in some African nations with high HIV prevalence rates.

Pathophysiology of Colitis

The underlying pathophysiology varies depending on the specific type of colitis, which is critical to consider when formulating a colitis differential diagnosis.

• Ulcerative Colitis (UC): Inflammation in UC typically involves the rectum in the vast majority (95%) of patients and extends proximally in a continuous manner. The disease can affect the entire colorectum (pancolitis) or be limited to the rectum (proctitis). In some cases, there may be limited involvement of the terminal ileum (backwash ileitis), which can pose diagnostic challenges in differentiating UC from Crohn’s disease.

• Ischemic Colitis: The extent and duration of hypoperfusion are key determinants of colonic injury in ischemic colitis. Reperfusion injury can also contribute significantly to tissue damage. Patients with ischemic colitis often have predisposing factors such as (1) comorbidities, including heart failure, atherosclerosis, systemic inflammatory response syndrome (SIRS), atrial fibrillation (potentially leading to emboli), concurrent malignancy, and hematological disorders (thrombosis), and (2) iatrogenic causes, such as abdominal aortic aneurysm repair, bowel preparation agents used for colonoscopy, and colonoscopy itself. Bowel ischemia can arise from two main mechanisms: diminished bowel perfusion due to low cardiac output (e.g., heart failure, shock) or occlusive disease, including atherosclerosis and embolism with inadequate collateral circulation.

• Drug-Induced Colitis: The pathophysiology and histological features of drug-induced colitis are variable and can mimic microscopic colitis or ischemic colitis. Identifying the offending drug is crucial in the colitis differential diagnosis.

• Colitis Secondary to Immune Deficiency Disorders: In the context of immune deficiency, various factors can contribute to colitis and diarrhea, including HIV infection itself, antiretroviral therapy, opportunistic infections (especially cytomegalovirus), and cryptosporidiosis.

Histopathology in Colitis

Histopathological examination of colonic biopsies plays a crucial role in the colitis differential diagnosis. While no single histological approach is universally standardized, the pattern-based approach described by Jessurun is widely considered practical and is currently recommended. This approach categorizes histological patterns as follows:

1. Acute Colitis: Typically associated with colonic infections and drug-induced injuries. Inflammation may be patchy or diffuse, characterized by mixed inflammatory cells and abundant neutrophils.
2. Focal Active Colitis: Frequently observed in drug-induced injuries but can also be a manifestation of inflammatory bowel disease, particularly Crohn’s disease.
3. Pseudomembranous Colitis Pattern: Strongly suggestive of C. difficile infection, although it can also be seen in other infections like Shigella, drug reactions, and radiation injury.
4. Hemorrhagic Colitis: Characteristically associated with enterohemorrhagic E. coli O157:H7. The lamina propria appears hemorrhagic and edematous, fibrin thrombi may be present in capillaries, and crypts may show ischemic injury.
5. Ischemic Colitis: Associated with acute ischemic events. The extent of mucosal injury influences the clinical presentation. Colonoscopy and biopsies are generally not required in cases of acute abdomen due to embolic occlusion or intestinal obstruction.

History and Physical Examination in Colitis

Patients presenting with colitis commonly report abdominal pain, watery diarrhea, fever, urgency, and bloody stools. A thorough history and physical examination are paramount in the colitis differential diagnosis. Clinicians should be vigilant for red flags, including:

• Patient’s age
• Hemodynamic instability
• Nocturnal diarrhea
• Tenesmus
• Urgency
• Unintentional weight loss
• Presence of comorbidities
• History of heart failure or arrhythmias (risk factors for ischemic colitis)
• Known autoimmune disorders
• Detailed medication history (including NSAIDs, recent antibiotics)
• Signs suggestive of toxic megacolon (e.g., abdominal distention, systemic toxicity)
• Anemia

In ulcerative colitis, extraintestinal manifestations associated with colitis and disease activity may include arthropathies, eye involvement (episcleritis, scleritis, uveitis), and skin lesions (erythema nodosum, pyoderma gangrenosum). Other reported extraintestinal manifestations in colitis include sacroiliitis, ankylosing spondylitis, hepatic dysfunction, and primary sclerosing cholangitis.

Evaluation of Colitis

The diagnosis of colitis relies on a combination of clinical assessment, laboratory investigations, endoscopy, and biopsy. Endoscopy and biopsy are not always the initial steps and should be considered after a careful evaluation of the patient’s clinical condition and initial examination findings. A systematic approach to evaluation is essential for accurate colitis differential diagnosis.

• Given that colonic infection is a common cause of colitis and can mimic inflammatory bowel disease clinically, microbiological studies and stool cultures for bacterial and parasitic pathogens should be prioritized as initial investigations.
• Basic laboratory workup should include a complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), arterial blood gases, activated partial thromboplastin time, serum albumin, total protein, blood urea nitrogen, creatinine, electrolytes, and purified protein derivative (PPD) test.
• D-lactate levels in blood have been suggested as a sensitive marker for colonic ischemia; however, this remains an experimental laboratory test.
• Electrocardiogram (ECG), transthoracic echocardiogram, and Holter monitoring may be indicated in patients suspected of ischemic colitis, particularly those with cardiac risk factors.
• Plain abdominal X-ray has limited diagnostic utility in colitis but can be helpful in identifying toxic megacolon, bowel obstruction, and intestinal perforation (pneumoperitoneum). Thumbprinting, indicative of mucosal edema, may be observed but is not specific for ischemic colitis.

Figure 1: Abdominal X-ray demonstrating necrotizing enterocolitis in an infant. Necrotizing enterocolitis is an important differential diagnosis in infants presenting with colitis symptoms.

• Multidetector computed tomography (MDCT) with thin sections can effectively demonstrate inflammatory changes in the colonic wall and aid in assessing the extent of disease. MDCT can also help differentiate ulcerative colitis from granulomatous colitis (Crohn’s disease) based on the location of involvement, extent, appearance of colonic wall thickening, and the presence of complications.
• Colonoscopy or proctosigmoidoscopy is crucial for definitive diagnosis. In microscopic colitis, the endoscopic appearance may be normal, although edema or erythema may be present. Ulceration should prompt consideration of alternative diagnoses, although it can occur in patients taking non-steroidal anti-inflammatory drugs.
• Other colonoscopic findings, varying with the etiology, include loss of the normal vascular pattern, granularity, friability, and ulceration.
• Specific serological tests may be ordered to aid in colitis differential diagnosis, including perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), which are often present in ulcerative colitis, and anti-Saccharomyces cerevisiae antibodies (ASCA), which can be found in both ulcerative colitis and Crohn’s disease. Carcinoembryonic antigen (CEA) levels may be elevated in active ulcerative colitis.
• Assessment of the extent, severity, and complications of colitis is essential for guiding management.

Treatment and Management of Colitis

Management strategies for colitis are tailored to the underlying etiology, which underscores the importance of accurate colitis differential diagnosis.

Not all cases of infectious colitis necessitate antibiotic therapy. For instance, mild to moderate C. jejuni or Salmonella infections are often self-limiting and do not require antibiotics. Antibiotic treatment with quinolone antibiotics is reserved for patients with dysentery and high fever suggestive of bacteremia. However, patients with AIDS, malignancy, transplant recipients, prosthetic implants, valvular heart disease, or those at extremes of age typically require antibiotic therapy. For mild to moderate C. difficile infection, metronidazole is the preferred initial treatment. In severe C. difficile infection, oral vancomycin is recommended. Complicated cases may require a combination of oral vancomycin and intravenous metronidazole. Cytomegalovirus (CMV) colitis is treated with valganciclovir, with the duration of therapy individualized based on the clinical presentation and laboratory parameters.

5-aminosalicylic acid (5-ASA) drugs are the cornerstone of treatment for inducing and maintaining remission in mild to moderate ulcerative colitis. The role of 5-ASA in Crohn’s disease management is less well-defined. Immunomodulators, such as azathioprine, 6-mercaptopurine, and methotrexate, are essential for maintenance therapy in patients with mild to moderately severe Crohn’s disease and frequently relapsing ulcerative colitis who have not responded to 5-ASA drugs. Biologic therapies, including tumor necrosis factor-alpha (TNF-α) inhibitors like infliximab, adalimumab, and certolizumab, are effective in managing Crohn’s disease, achieving disease control, and long-term maintenance. Corticosteroids are effective for inducing remission in inflammatory bowel disease but are not recommended for maintenance therapy due to significant side effects. Surgical intervention is considered for patients who do not respond to medical management.

In microscopic colitis, discontinuation of any potentially causative medications and smoking cessation are crucial initial steps. While anti-diarrheal agents, bismuth subsalicylate, or cholestyramine may provide symptomatic relief, budesonide is effective for inducing remission and is often the first-line medication. In patients for whom budesonide is not suitable, bismuth salicylate or mesalamine are alternative options.

Patients with ischemic colitis without signs of peritonitis may be managed medically with intravenous fluid resuscitation, optimization of cardiac output, supplemental oxygen, bowel rest, parenteral nutrition, broad-spectrum antibiotics to cover aerobic and anaerobic coliform bacteria, and close monitoring. Failure of medical management or the development of peritonitis or intestinal perforation necessitates surgical intervention and bowel resection.

For tuberculous colitis, a nine-month anti-tuberculosis regimen is recommended, typically starting with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for the remaining 7 months. Regular follow-up is essential to assess treatment response.

Differential Diagnosis of Colitis

A comprehensive colitis differential diagnosis is crucial for accurate management. Conditions to consider include:

• Irritable bowel syndrome (IBS)
• Celiac disease (especially in patients with persistent diarrhea despite a gluten-free diet; consider microscopic colitis in these cases)
• Colorectal cancer
• Diverticulitis
• Toxic megacolon (can be both a complication and a differential diagnosis in severe cases)
• Viral or bacterial gastroenteritis (self-limiting, usually lacks the chronic or relapsing nature of other colitides)
• Other types of colitis (as detailed in the Etiology section)

Figure 2: Microscopic image illustrating Clostridioides difficile colitis. C. difficile infection is a critical consideration in the differential diagnosis of colitis, particularly in patients with recent antibiotic use or healthcare exposure.

Complications of Colitis

Potential complications of colitis can be severe and include:

• Intestinal perforation
• Bowel strictures, fistulas, abscesses, and intestinal obstruction
• Fecal incontinence
• Pelvic abscess
• Enterocutaneous fistulas, particularly in Crohn’s disease
• Pouchitis (in patients with ileal pouch-anal anastomosis for UC)
• Guillain-Barré syndrome (associated with Campylobacter jejuni colitis, cytomegalovirus colitis, and rarely reported in ulcerative colitis)
• Hemolytic uremic syndrome (associated with enterohemorrhagic E. coli and Shigella infections)
• Encephalopathy, seizures (associated with Shigella infection)

Toxic megacolon is a serious, though uncommon, complication of colitis, characterized by total or segmental nonobstructive colonic dilatation with systemic toxicity. It carries a significant mortality rate of approximately 19%. Ulcerative colitis and pseudomembranous colitis are well-known conditions that can progress to toxic megacolon in over 60% of cases. Campylobacter and Shigella colitis can also lead to toxic megacolon.

Clinical Pearls and Key Considerations in Colitis

The symptoms of colitis are often nonspecific, necessitating a detailed medical history, thorough physical examination, and appropriate laboratory investigations. Endoscopic evaluation with mucosal biopsy is often essential to confirm the diagnosis and exclude inflammatory bowel disease-associated colitis, particularly when colitis differential diagnosis includes IBD.

Enhancing Healthcare Team Outcomes in Colitis Management

Colitis, depending on its underlying cause, can range from a self-limited condition to a life-threatening, chronic, or recurrent illness. Patients with chronic and recurrent colitis require ongoing, lifelong monitoring. General practitioners play a vital role in the early diagnosis of colitis, providing ongoing support to patients, and assisting with lifestyle modifications such as smoking cessation and disease management. Nurses are crucial in educating and empowering patients to take responsibility for their condition, providing knowledge about their pathology and medications. Pharmacists contribute by being aware of medications that can induce colitis and assisting in managing potential drug-related complications. Nurses and pharmacists should promptly report any adverse events or complications to the clinical team. Surgeons play a critical role in managing specific colitis-related emergencies and in cases that fail to respond to medical therapy. Patients with chronic colitis are at increased risk of developing depression and anxiety, highlighting the need for integrated mental health support. Effective management of colitis and optimization of patient outcomes rely on the collaborative efforts of a multidisciplinary interprofessional healthcare team.

Review Questions

Figure 3

Figure 3: Radiograph of an infant with necrotizing enterocolitis. This image illustrates the radiographic findings in necrotizing enterocolitis, a condition that should be considered in the differential diagnosis of colitis in neonates and infants.

Figure 4

Figure 4: Gross pathology of neonatal necrotizing enterocolitis showing intestinal necrosis, pneumatosis intestinalis, and perforation. This image highlights the severe intestinal damage that can occur in necrotizing enterocolitis, emphasizing the need for prompt diagnosis and intervention.

Figure 5

Figure 5: Micrograph of Clostridioides difficile bacteria in colitis. This microscopic view demonstrates the presence of C. difficile bacteria in the colonic mucosa, confirming infectious colitis caused by this pathogen.

Figure 6

Figure 6: Endoscopic image of pseudomembranous colitis. This image shows the characteristic pseudomembranes in the colon, a hallmark of Clostridioides difficile infection and a key diagnostic feature.

Figure 7

Figure 7: Pathology outline of amebic colitis. This image provides a pathological overview of amebic colitis, highlighting the tissue damage and inflammatory response associated with Entamoeba histolytica infection.

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Disclosures: Samy Azer declares no relevant financial relationships with ineligible companies.

Disclosures: Yan Sun declares no relevant financial relationships with ineligible companies.