What should be included in the differential diagnosis for a patient with intermittent bloating and epigastric/subcostal (below the ribs) pain, with negative tests for giardia, other parasites, and Helicobacter pylori (H. pylori)?

Differential Diagnosis for Intermittent Bloating and Epigastric/Subcostal Pain

The differential diagnosis should prioritize functional dyspepsia, irritable bowel syndrome, celiac disease, bile acid diarrhea, small intestinal bacterial overgrowth (SIBO), pancreatic exocrine insufficiency, and gastroparesis, with consideration of structural causes including peptic ulcer disease and chronic pancreatitis. 1

Primary Functional Disorders

Functional Dyspepsia (FD)

• Epigastric pain as the predominant symptom strongly suggests acid-related functional dyspepsia, which responds to proton pump inhibitor (PPI) therapy 1
• Bloating and fullness are characteristic features that may overlap with gastroparesis, as these conditions exist on the same clinicopathological spectrum of gastric neurodysfunction 1
• The diagnosis presumes absence of structural or biochemical explanations for symptoms 1

Irritable Bowel Syndrome (IBS)

• Bloating is a cardinal feature of IBS, occurring alongside abdominal pain and altered bowel habits 1
• The intermittent nature (2-3 week episodes) fits the relapsing-remitting pattern typical of IBS 1
• Passage of mucus and feeling of abdominal distention support this diagnosis 1

Malabsorptive and Metabolic Causes

Celiac Disease

• Tissue transglutaminase IgA with total IgA levels should be tested, as celiac disease commonly presents with bloating and epigastric discomfort 1
• Small bowel biopsy confirms diagnosis if serology is positive 1
• In some patients, fructans in gluten-rich foods rather than gluten itself cause symptoms 1

Bile Acid Diarrhea (BAD)

• BAD is a common cause of functional diarrhea and should be considered even without overt diarrhea 1
• 48-hour fecal bile acid excretion or serum C4/FGF19 testing can establish diagnosis 1
• This is particularly relevant given the intermittent nature of symptoms 1

Pancreatic Exocrine Insufficiency (PEI)

• Fecal elastase testing should be performed if chronic abdominal pain persists, as PEI can cause bloating accompanied by pain 1
• Note that falsely low fecal elastase may occur secondary to diarrhea itself 1

Infectious and Microbial Causes

Small Intestinal Bacterial Overgrowth (SIBO)

• Despite negative parasite testing, SIBO remains a consideration for intermittent bloating and pain 1
• Hydrogen and methane breath testing using glucose substrate is preferred over lactulose 1
• Empiric treatment with rifaximin may be warranted in high-risk patients with chronic symptoms 1, 2

Post-Giardia IBS

• Even with negative giardia testing, post-infectious IBS can develop after giardiasis 3
• The large majority of patients with symptomatic giardiasis are affected by IBS and symptoms may persist despite parasite eradication 3
• Consider that standard stool testing may miss intraepithelial giardiasis 4

Structural and Motility Disorders

Gastroparesis

• Bloating correlates with nausea, abdominal fullness, and pain in approximately 40% of gastroparesis patients 1
• Gastric scintigraphy should only be considered if severe nausea or vomiting is present, not for bloating alone 1
• Symptoms do not correlate with degree of gastric emptying delay 1, 2

Peptic Ulcer Disease

• Upper endoscopy should be considered in patients older than 40 years with dyspeptic symptoms and bloating, especially in regions with high H. pylori prevalence 1
• Despite negative H. pylori testing, H. pylori-negative peptic ulcers can occur and require full-dose PPI therapy 1

Chronic Pancreatitis

• Bloating accompanied by pain may indicate chronic pancreatitis, warranting fecal elastase testing 1

Carbohydrate Malabsorption

Lactose and Fructose Intolerance

• Lactose intolerance affects 51% and fructose intolerance affects 60% of patients with bloating 2
• Lactose/dextrose hydrogen breath testing can identify these conditions 1
• A low-FODMAP diet trial for 3-4 weeks may be both diagnostic and therapeutic 2

Critical Diagnostic Algorithm

Step 1: Screen for alarm features

• Weight loss >10%, GI bleeding, iron-deficiency anemia, persistent vomiting, or family history of IBD/cancer mandate immediate investigation 2

Step 2: Age-appropriate testing

• Patients >40-50 years with dyspeptic symptoms should undergo upper endoscopy 1
• Younger patients without alarm features can proceed with non-invasive testing 1

Step 3: Initial laboratory evaluation

• Tissue transglutaminase IgA with total IgA for celiac disease 1
• Complete blood count and comprehensive metabolic panel only if alarm symptoms present 2
• Fecal elastase if pain is prominent 1

Step 4: Consider empiric therapy

• Full-dose PPI (omeprazole 20 mg daily) for epigastric pain-predominant symptoms 1
• Low-FODMAP diet trial for bloating-predominant symptoms 2
• Response to therapy helps confirm diagnosis 1

Common Pitfalls to Avoid

• Do not over-test in the absence of alarm symptoms, as extensive imaging and motility testing have low yield 1, 2
• Do not assume gastroparesis based on symptoms alone, as bloating and fullness do not correlate with gastric emptying delay 2
• Do not ignore the possibility of multiple concurrent conditions, such as functional dyspepsia with carbohydrate malabsorption 1
• Remember that PPIs can cause false-negative H. pylori testing if used within 2 weeks of testing 1
• Consider that negative stool testing does not completely exclude giardiasis, as intraepithelial forms may be missed 4