Fatigue Common But Often Overlooked in Cholestasis, Study Finds

New research suggests fatigue is common in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), underscoring the importance of quantifying this symptom in patients’ clinical workup and considering it in therapeutic decision-making.1

Leveraging data from 2 cohorts of patients with PBC and PSC recruited from the Medical Universities in Szczecin and Warsaw in Poland, the study found fatigue was more common among patients with PBC but disproportionately impacted females with PSC. Of note, fatigue was not modulated by disease duration and did not improve with response to ursodeoxycholic acid (UDCA) but was significantly associated with itch.1

“The etiology of fatigue in the setting of cholestatic conditions like PBC and PSC is poorly understood thus there is no effective treatment,” Piotr Milkiewicz, MD, DSc, MRCP, a professor in the department of general, transplant, and liver surgery at the Medical University of Warsaw, and colleagues wrote.1

The advent of peroxisome proliferator-activated receptor agonists for the second-line treatment of PBC, including elafibranor and seladelpar, have introduced effective therapies for addressing itch. While pruritus has become a more widely recognized symptom of cholestasis and a therapeutic target for new drugs in development, fatigue has garnered less attention and continues to be overlooked, especially in patients with PSC.2,3

To address the sparsity of data regarding fatigue in patients with cholestasis, investigators analyzed data from 2 cohorts encompassing a total of 1267 individuals, 514 with PBC and 753 with PSC, recruited from the Medical Universities in Szczecin and Warsaw in Poland. In each cohort, quality of life was measured using the PBC-40 questionnaire.1

Investigators noted the PBC cohort was significantly older (56 vs 32; P <.001), encompassed more female patients (91% vs 34%; P <.001), and had a greater number of patients with cirrhosis (38% vs 20%; P <.001) than the PSC cohort. They also called attention to significant differences in fatigue between the cohorts, with higher scores reported among those with PBC (median, 30; range, 11–54) as compared to PSC (median, 23; range, 11–55) (P <.001).1

Among patients with PBC, 37% reported clinically significant fatigue, defined as >33 points in the fatigue domain of the PBC-40 questionnaire. In the PSC cohort, clinically significant fatigue was present in 22% of patients. Of note, while females reported greater fatigue than males in both cohorts, the difference was only significant in the PSC group (P <.001).1

Further analysis revealed that in patients with PSC, fatigue correlated with serum alkaline phosphatase (P <.001) and gamma-glutamyl transferase (P = .027). In patients with PBC, fatigue was greater in those with cirrhosis (P = .018).1

Investigators noted fatigue was not modulated by disease duration in either cohort, and in patients with PSC, it did not correlate with inflammatory bowel disease (both P >.05). Additionally, the pointed out UDCA response did not have a significant effect on fatigue levels in the PBC cohort (P >.05).1

Like fatigue, itch severity was greater in patients with PBC than those with PSC (P = .001). Investigators also found a significant correlation between fatigue and itch severity in both cohorts (both P <.001). Specifically, patients with the lowest itch also had the lowest fatigue (P <.001).1

“Although no established therapy for fatigue in the setting of cholestasis exists, new PBC medications might improve not only the prognosis in this condition but also show some promise in reducing fatigue. Therefore, we believe that quantifying fatigue should be included in the clinical workup of patients with chronic cholestasis and therapeutic decisions,” investigators concluded.1 “Further research is needed to establish new therapies for fatigue in PBC and PSC.”

References

1. Kruk B, Raszeja-Wyszomirska J, Krawczyk M, Milkiewicz P. Fatigue and itch severity in patients with PBC and PSC: Prospective analysis of two large cohorts. Eur J Clin Invest. doi:10.1111/eci.70041

2. Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed April 8, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

3. Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed April 8, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis