Chronic diarrhea is one of the most common reasons for gastroenterology referrals. The differential diagnosis for diarrhea is broad, with etiologies ranging from infection to functional disorders of gut-brain interaction. This article will guide healthcare practitioners through the top five differential diagnoses for patients struggling with diarrhea.

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Overview of Diarrhea

Diarrhea is a common gastrointestinal symptom characterized by the frequent passage of loose or watery stools. Diarrhea is broadly characterized based on its chronicity. Acute diarrhea, often caused by infections, is the acute onset of three or more loose stools daily for no more than two weeks. Persistent diarrhea lasts 2-4 weeks, and chronic diarrhea persists longer than one month. 

The pathophysiology of diarrhea involves physiologic imbalances that cause disruptions in the normal absorption and secretion processes within the intestines. Gastrointestinal infections increase fluid secretion and reduce absorption, resulting in loose stools. Chronic diarrhea, on the other hand, may involve more complex mechanisms such as inflammation or malabsorption. (27) 

Obtaining a thorough patient history is of the utmost importance in evaluating diarrhea. Inquiring about the onset, frequency, characteristics of symptoms, and potential triggers can aid in identifying the underlying cause of loose and frequent stools. A physical examination helps assess the patient's overall health, hydration status, and signs of systemic illness. Diagnostic tests, including stool analysis and imaging studies, may be employed based on the clinical findings. The classification of diarrhea based on the duration of symptoms and etiology is important because it determines the treatment of diarrhea.

The Top 5 Differential Diagnoses of Diarrhea

Establishing a broad and prioritized list of potential causes for diarrhea is paramount to effective clinical management. Infectious gastroenteritis, inflammatory bowel disease, irritable bowel syndrome, celiac disease, and medication-induced diarrhea stand out as primary considerations due to their prevalence. By considering these top five differentials in the initial assessment, healthcare practitioners can strategically navigate the diagnostic process that ensures a systematic approach, aids in expeditious identification of the underlying cause, and facilitates timely interventions, ultimately optimizing patient care and outcomes.

1. Infectious Gastroenteritis

Infectious gastroenteritis stands as a prominent contributor to diarrhea. In the United States alone, gastroenteritis affects 179 million people annually. Infectious gastroenteritis is inflammation in the stomach and intestines due to an infection from a bacteria, virus, parasite, or fungus that causes acute symptoms like nausea, vomiting, abdominal pain, and diarrhea. Viruses cause 60% of all gastroenteritis cases.

Recent travel to foreign countries, changes in diet, and ingestion of undercooked foods or unfiltered water should raise suspicion for infectious diarrhea. Associated symptoms, such as fever and vomiting, and time of onset can further guide the differential diagnosis. (38) 

Infectious gastroenteritis can be diagnosed clinically, and diagnostic tests for gastroenteritis are not required. However, stool cultures and polymerase chain reaction (PCR) tests are valuable tools for diagnostic confirmation to identify the specific pathogen. When parasites are suspected, stool ova and parasite examination may be warranted. Other tests that could be considered include serum chemistry, C-reactive protein (CRP), and complete blood count. (32, 35, 38) 

Gastroenteritis management strategies focus on supportive care to address dehydration and electrolyte imbalance, particularly in severe cases. Hydration through oral rehydration solutions or intravenous fluids may be necessary. Antimicrobial therapy, when indicated, targets the specific pathogen identified. However, judicious use is essential to prevent antibiotic resistance and avoid unnecessary treatments for viral infections. Symptomatic treatment with a BRAT diet, ginger, peppermint, and over-the-counter medications (e.g., loperamide or bismuth subsalicylate) is effective and may be considered in uncomplicated cases. (21, 38)

2. Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal (GI) tract with a complex, multifactorial etiology that manifests as recurrent symptoms of diarrhea, abdominal pain, GI bleeding, and weight loss. Chronic diarrhea is the hallmark symptom associated with IBD, seen in 80% of cases. (2) 

IBD encompasses Crohn's disease and ulcerative colitis. Crohn's disease can affect any part of the GI tract, and diarrhea may be accompanied by right lower quadrant abdominal pain, fatigue, and extraintestinal symptoms like joint pain or skin lesions (30). Ulcerative colitis primarily affects the colon and rectum, presenting with bloody diarrhea, fecal urgency, and tenesmus.

Distinguishing IBD from other types of diarrhea requires a comprehensive patient history, including the duration and characteristics of symptoms. Laboratory tests may indicate elevated inflammatory markers, such as CRP or fecal calprotectin. The Celiac, IBS, and Crohn's Assay (CICA) by Cell Science Systems evaluates genetic and serological markers for celiac disease and Crohn's disease, helping to distinguish IBD from other diarrheal diseases.

Key diagnostic approaches for IBD involve endoscopic evaluation of the intestines with colonoscopy and endoscopy to visualize the extent and severity of inflammation. Biopsies obtained during endoscopy aid in confirming the diagnosis and differentiating between Crohn's disease and ulcerative colitis. Imaging studies, including computed tomography (CT) or magnetic resonance imaging (MRI), may be employed to assess the extent of involvement and complications. (26)

The treatment goals for IBD include inducing and maintaining remission, controlling GI inflammation, restoring nutritional deficits, and treating symptoms. Conventional treatment of IBD encompasses pharmacologic anti-inflammatory, immunosuppressant, and biologic medications. Complementary and integrative therapies, including dietary and lifestyle modifications, stress management, and natural supplements, can be used as alternatives to or in conjunction with conventional interventions. 

3. Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) is a functional GI disorder (FGID) characterized by chronic abdominal pain and altered bowel habits in the absence of identifiable organic pathology. The Rome IV criteria provide guidelines for the diagnosis of IBS, emphasizing the presence of recurrent abdominal pain on average at least one day per week in the last three months, associated with two or more of the following: related to defecation, associated with a change in frequency of stool, or associated with a change in form (appearance) of stool. IBS-D is a subtype of IBS that affects one-third of people with IBS, in which at least 25% of abnormal bowel movements are diarrhea. 

Given the overlap of symptoms between IBS and other organic gastrointestinal diseases, it is imperative to rule out organic pathologies through a comprehensive evaluation, including laboratory tests, imaging studies, and endoscopic procedures. This helps to ensure accurate diagnosis and appropriate management of patients presenting with gastrointestinal symptoms suggestive of IBS. Specialty testing can help pinpoint dysbiotic patterns, alterations in GI motility and permeability, immune dysfunction, and neurological imbalances that often underlie FGIDs. (9) 

The management of IBS entails a multidimensional approach tailored to individual patient needs. Dietary modifications, such as the low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, can help alleviate symptoms by reducing intake of poorly absorbed carbohydrates that ferment in the gut and contribute to bloating and discomfort. Modulating the gut-brain axis with stress management techniques, adaptogenic herbs, and probiotics helps to manage the psychological component of IBS symptoms.

Pharmacotherapy options for IBS include antispasmodics to alleviate abdominal pain and discomfort, antidiarrheals to regulate bowel movements, and antidepressants or antianxiety medications to address associated mood disorders and improve overall symptom control.

4. Celiac Disease

Celiac disease (CD) is an autoimmune disorder characterized by an aberrant immune response to gluten ingestion, a protein found in wheat, barley, and rye. This immune reaction leads to inflammation and damage to the small intestine, resulting in diarrhea and malabsorption of nutrients. 

The clinical presentation of CD may include chronic diarrhea, weight loss, abdominal pain, and fatigue. Individuals with a medical history of autoimmune diseases, such as type 1 diabetes and multiple sclerosis, are at an elevated risk of developing celiac disease. Dermatitis herpetiformis, characterized by itchy, blistering skin lesions, is another unique feature often observed in individuals with CD.

Non-invasive diagnostic tests for celiac disease include serologic assays, primarily measuring antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptide. Elevated levels of these antibodies indicate an immune response triggered by gluten ingestion. A comprehensive celiac panel, such as the Celiac Profile by Genova Diagnostics, measures additional antibodies associated with CD pathology, increasing the accuracy of serologic testing. Definitive diagnosis of CD requires endoscopic evaluation with small intestine biopsies. During endoscopy, histological changes such as villous atrophy and crypt hyperplasia can be observed in the small intestine, solidifying the diagnosis.

Celiac disease management requires strict, life-long adherence to a gluten-free diet. Additionally, some individuals may require the elimination of cross-reactive foods. A functional medicine treatment protocol supplements this diet with gut-healing interventions, such as probiotics and anti-inflammatory dietary/herbal supplements. (40) 

5. Medication-Induced Diarrhea

Over 700 drugs have diarrhea as a listed side effect. The most common medications implicated in causing diarrhea include antibiotics, laxatives, magnesium-containing antacids, lactose- and sorbitol-containing products, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, chemotherapy agents, and antihypertensive medications (e.g., beta-blockers, ACE-inhibitors). Antibiotics are responsible for 25% of drug-induced diarrhea cases. The mechanisms contributing to medication-induced diarrhea involve alterations in gut motility, changes in fluid secretion, or disruptions to the intestinal flora. Many times, multiple mechanisms are involved simultaneously. (6) 

Drug-induced diarrhea can be easily overlooked, so the importance of a comprehensive medication and supplement review cannot be overstated in patients presenting with diarrhea. Healthcare practitioners should thoroughly assess the patient's medication and supplement list, considering potential culprits and the relationship between the onset of symptoms and changes in medications or dosages.

For treatment, your healthcare provider may recommend stopping or modifying the dose of the causative agent. Most cases of drug-induced diarrhea resolve spontaneously within a few days after withdrawal or a dose reduction of the drug. It is not always possible to discontinue medications, so always talk to your healthcare provider before making any medication changes if you suspect you have medication-induced diarrhea. Probiotics can help restore the balance of the gut microbiota disrupted by antibiotics. Maintaining adequate hydration and incorporating dietary modifications, such as increasing fiber intake, can alleviate symptoms. (3, 39) 

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Key Takeaways:

A systematic approach to evaluating and treating diarrhea should begin with creating a broad differential diagnosis. To narrow the differential, healthcare professionals should employ a systematic methodology, incorporating thorough patient history, meticulous physical examinations, and appropriate diagnostic testing. By considering various potential causes, including infectious, inflammatory, and functional etiologies, practitioners can accurately identify the underlying condition and tailor treatment plans accordingly. This personalized approach facilitates timely interventions and improves patient outcomes by addressing the factors contributing to diarrhea. Emphasizing the integration of clinical assessments and diagnostic tools in an organized manner underscores the significance of precision diagnostics and the role of tailored treatment plans in optimizing patient care.