Fatigue as an Extra-Intestinal Manifestation of Celiac Disease: A Systematic Review

Abstract

Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and “constant tiredness”. All of these symptoms should consequently lead the clinicians to consider celiac disease as a potential etiopathogenetic cause. Although the pathophysiology of celiac disease is well documented, the actual mechanisms for disease presentation(s) are less well understood. We here address the topic of fatigue in celiac disease. A systematic literature search identified 298 papers of which five met the criteria for full evaluation. None of the reviewed papers were of high quality and had several methodological weaknesses. We conclude that there is an unmet need to study the contributing factors and management of fatigue in celiac disease.

Fatigue: a frequent and biologically based phenomenon in newly diagnosed celiac disease

“…Most previous studies reporting the prevalence of fatigue have used a simple question asking patients whether or not they suffered from fatigue 21 , 40 – 47 ; only one study applied a disease-specific fatigue instrument (Celiac Disease Patient Reported Outcome, Non-gastrointestinal domain) 48 . The inconsistencies in rating and reporting could thus be a reason for the large variations and discrepancy in previous studies, ranging from 8 to 82% 24 , 25 .…”

“…These extraintestinal manifestations may result from both aberrant immune responses and malabsorption 22 ; extreme tiredness, and fatigue have been among the most commonly reported extraintestinal complaints 20 , 21 , 23 . This contrasts with the traditional concept of the disease, possibly explaining why current literature regarding fatigue in celiac disease is sparse and inconsistent 24 , 25 .…”

How Metabolomics Provides Novel Insights on Celiac Disease and Gluten-Free Diet: A Narrative Review

“…Serum analyses from U-CD showed an increased concentration of glucose ( Bertini et al, 2009 ; Bernini et al, 2011 ; Upadhyay et al, 2020 ) but reduced levels of pyruvate and lactate ( Bertini et al, 2009 ; Fathi et al, 2013 ). This energetic impairment directly impacts the weakness and the chronic fatigue reported by U-CD at diagnosis ( Jelsness-Jørgensen et al, 2018 ) and opens the way to another signature commonly observed in selected studies, that is, the high synthesis/utilization of lipids and ketone bodies as the energy sources instead of glucose. Some of the selected studies assessed higher levels of ketogenic metabolites in U-CD than in HC ( Bertini et al, 2009 ; Di Cagno et al, 2009 ; Bernini et al, 2011 ; Upadhyay et al, 2020 ).…”

“…When evaluating the same individuals after 12 months of GFD, long-chain (C20–22) PUFAs increased although this variation was not sufficient to reach the levels found in HC. Long-chain (C20–22) PUFAs are important for optimal metabolism while deficiencies might contribute to the disease onset, including psychiatric diseases and depression that, indeed, are manifestations usually reported by U-CD ( De Palma et al, 2014 ; Jelsness-Jørgensen et al, 2018 ). Impairments in FAs determined by CD were also argued by Jamnik et al (2018) .…”

Celiac Disease

“…There is no standard definition for fatigue and studies have used different instruments to measure it 58 . Chronic fatigue may be an indication to screen for CeD, since it was found more often among undiagnosed cases of CeD 59 .…”