Why is a patient with ulcerative colitis (UC) experiencing fatigue?

Fatigue in Ulcerative Colitis: Causes and Evaluation

Patients with UC experience fatigue due to multiple mechanisms including pro-inflammatory cytokines directly affecting the central nervous system, anemia, nutritional deficiencies, and subclinical disease activity—importantly, fatigue can persist even during clinical remission and does not necessarily correlate with gastrointestinal symptom control. 1, 2

Primary Pathophysiologic Mechanisms

Pro-inflammatory cytokines are the fundamental driver of fatigue in UC, directly inducing central nervous system changes that generate fatigue independent of peripheral disease activity. 2 The immune system, central and autonomic nervous systems, and neuroendocrine system all contribute to fatigue induction and maintenance. 2

Key Clinical Characteristics

• Fatigue in UC is typically chronic, irreversible, not alleviated by rest, and not related to exertion. 2
• Over 40% of patients with inactive UC experience persistent fatigue despite being in clinical remission. 2
• Fatigue severity does not necessarily correlate with disease activity and can persist when gastrointestinal symptoms are controlled. 1, 2

Systematic Evaluation Approach

Initial Screening

Screen all UC patients for fatigue using a visual analogue scale (0-10), with scores ≥4 warranting comprehensive evaluation. 1, 3 The European Crohn's and Colitis Organisation specifically recommends this threshold for triggering detailed workup. 1

Reversible Causes to Investigate

Anemia and Iron Deficiency:

• Anemia significantly contributes to fatigue and requires thorough investigation and treatment. 2
• Iron deficiency, even without anemia, may contribute to fatigue. 3
• Order complete blood count and iron studies. 3

Nutritional Deficiencies:

• UC patients are at high risk for multiple nutrient deficiencies due to chronic inflammation, malabsorption, and impaired muscle strength. 2
• Check comprehensive nutritional panel: vitamin B6, B12, folate, ferritin, zinc, magnesium, calcium, vitamin D, copper, and phosphate. 2
• Low serum vitamin D, IGF-1, and magnesium specifically correlate with muscle fatigue and self-reported fatigue severity. 2
• Vitamin B12 and folate deficiencies should be replenished with oral or intramuscular supplementation. 3

Other Metabolic Factors:

• Thyroid dysfunction should be evaluated with thyroid function tests. 1, 3
• Electrolyte disturbances require assessment via comprehensive metabolic panel. 1, 3

Disease Activity:

• Assess for subclinical disease activity, as underlying inflammation correlates with fatigue severity even when overt symptoms are absent. 1
• Consider fecal calprotectin or other biomarkers to detect subclinical inflammation. 4

Concurrent Symptoms:

• Evaluate sleep disturbance through structured sleep-wake schedule assessment. 1, 3
• Screen for psychological distress including depression. 1, 3
• Review medication side effects—notably, fatigue is listed as a common adverse reaction (6% incidence) with vedolizumab treatment. 5

Management Algorithm

Step 1: Address Underlying Inflammation

If subclinical disease activity is present, optimize UC treatment first, as disease activity correlates with fatigue severity. 1

Step 2: Correct Nutritional Deficiencies

• Treat anemia with appropriate iron supplementation. 3
• Replenish vitamin B12 deficiency with oral or intramuscular supplementation. 3
• Correct vitamin D deficiency. 3
• All nutrient deficiencies should be corrected with dietitian referral when appropriate. 2
• Re-evaluate laboratory parameters 3 months after initiating supplementation to confirm correction. 3

Step 3: Address Thyroid and Electrolyte Abnormalities

Optimize thyroid dysfunction and electrolyte abnormalities as identified. 3

Step 4: Psychological Interventions

Consider solution-focused therapy or cognitive behavioral therapy, which showed temporary benefit in IBD-related fatigue with effects lasting up to 3 months post-therapy. 1, 3 Response should be monitored at 3-month intervals, recognizing that maintenance therapy may be needed to sustain benefits. 3

Step 5: Lifestyle Modifications

• Promote regular exercise, which has shown positive effects on physical fatigue. 1, 3
• Start with low-intensity activities and gradually increase as tolerated. 3
• Optimize sleep hygiene through structured sleep-wake schedules and limiting caffeine. 3

Important Clinical Caveats

The most critical pitfall is assuming fatigue will resolve with control of gastrointestinal symptoms alone. The British Society of Gastroenterology specifically notes that fatigue does not necessarily correlate with disease activity and can persist even when gastrointestinal symptoms are controlled. 1 This means aggressive evaluation for reversible causes is mandatory even in patients with well-controlled UC.

Fatigue severity should be reassessed at each visit using the same visual analogue scale for consistency. 3 This allows tracking of response to interventions and identifies when additional evaluation or treatment modifications are needed.