Fatigue and liver transplantation in patients with primary biliary cirrhosis
Authors: Evangelos Kalaitzakis, Einar Björnsson
Journal: Journal of Hepatology (2014)

The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: A prospective studyJournal of HepatologyVol. 59Issue 3PreviewThe role of liver transplantation (LT) for the relief of fatigue in patients with primary biliary cirrhosis (PBC) is unclear, and while many centers exclude fatigue as an indication for transplantation, there have been no studies to prospectively evaluate the impact of LT on fatigue. We aimed at assessing the severity of fatigue in LT candidates with PBC and the impact of LT on fatigue. Full-Text PDF Reply to: “Fatigue and liver transplantation in patients with primary biliary cirrhosis”Journal of HepatologyVol. 60Issue 6PreviewWe would like to thank Kalaitzakis et al. [1] for the comments on our article on the effect of liver transplantation (LT) on fatigue in patients with primary biliary cirrhosis (PBC) [2]. They confirm in an independent PBC cohort that fatigue remains a problem after LT. They also address some important issues, such as the need for an accurate assessment of hepatic encephalopathy (HE) before LT in patients with PBC, and that fatigue may not be specific to PBC. Full-Text PDF Open Access We read with great interest the paper of Carbone et al. [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] on fatigue in patients with primary biliary cirrhosis (PBC) and the role of liver transplantation. They performed a prospective, longitudinal study investigating fatigue in 49 adult cirrhotic patients with PBC at listing and at 6, 12, and 24 months after transplantation. They found that fatigue scores, as assessed by means of the PBC-40 questionnaire, improved substantially following transplantation but remained higher compared to community controls two years post-transplant [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. In all, 89% of patients had moderate to severe fatigue before transplantation, which was also true for 48% and 44% at one and two years post-transplant respectively [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. We have recently reported that although fatigue improves following transplantation in unselected cirrhotic patients, 37% are physically fatigued 1 year post-transplant [[2]Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar], which is in accordance with previous studies [3Aadahl M. Hansen B.A. Kirkegaard P. Groenvold M. Fatigue and physical function after orthotopic liver transplantation.Liver Transpl. 2002; 8: 251-259Crossref PubMed Scopus (79) Google Scholar, 4van Ginneken B.T.J. van den Berg-Emons R.J.G. van der Windt A. Tilanus H.W. Metselaar H.J. Stam H.J. et al.Persistent fatigue in liver transplant recipients: a two-year follow-up study.Clin Transplant. 2010; 24: E10-E16Crossref PubMed Scopus (48) Google Scholar]. In this prospective longitudinal study [[2]Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] no patients with hepatic encephalopathy grade >I were included as they could not complete the study questionnaires. Encephalopathy was assessed clinically (West-Haven criteria) and by means of the number connection tests A and B [[2]Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. We found that fatigue severity in unselected cirrhotic patients worsened with worsening encephalopathy (from none to minimal and overt) [[2]Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. Only 12 patients included in this paper had PBC (median age 54 (interquartile range 39–60); 9 female) and 10 reached 1 year post-transplant (1 patient died on the transplant list and another during the first post-transplant year). Fatigue was assessed by means of the fatigue impact scale, a 40-item questionnaire, which has been validated in PBC [[5]Prince M.I. James O.F. Holland N.P. Jones D.E. Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use.J Hepatol. 2000; 32: 368-373Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Fatigue data from these patients (not reported separately in the initial report) in comparison to non-PBC cirrhotic patients are shown in Table 1. Fatigue scores across all domains did not differ significantly between the two groups neither pre- nor post-transplant (Table 1). All domain and total fatigue scores improved in both groups at 1 year post-transplant, but in the PBC group, this was mainly due to an improvement in the cognitive fatigue domain score (Table 1). Carbone and colleagues also found that the cognitive domain of the PBC-40 improved post-transplant [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar], which may have been due to an improvement in hepatic encephalopathy. Although they identified two patients with moderate encephalopathy (both with severe fatigue one of whom improved post-transplant), there was no formal assessment of (minimal) hepatic encephalopathy. This is surprising as encephalopathy in patients with cirrhosis is a well-known cause of lethargy and fatigue. It is also unclear whether any patients were excluded due to inability to fill in the study questionnaire as a result of hepatic encephalopathy [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. As the authors argue, fatigue severity may not be related to non-cirrhotic PBC severity at a group level [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] but it appears to be related to liver disease severity in cirrhosis in general [[2]Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. Also, our data showing that improvement in fatigue post-transplant in PBC patients was attributed mainly to improvement in cognitive fatigue, and the fact that the two patients with moderate encephalopathy in the current study had severe fatigue with one improving post-transplant [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar], indicate that encephalopathy could be an important factor leading to fatigue at least for some cirrhotic patients with PBC.Table 1Fatigue scores at pre-transplant evaluation and 12 months following liver transplantation in patients with cirrhosis due to PBC and those with cirrhosis without PBC.Data are presented as median (interquartile range).FIS, fatigue impact scale.The p values of Mann-Whitney tests are reported in the table.ap = 0.092 vs. pre-transplant.bp = 0.114 vs. pre-transplant.cp = 0.021 vs. pre-transplant.dp = 0.047 vs. pre-transplant.ep <0.05 vs. pre-transplant (related-samples Wilcoxon signed rank test). Open table in a new tab Data are presented as median (interquartile range). FIS, fatigue impact scale. The p values of Mann-Whitney tests are reported in the table. ap = 0.092 vs. pre-transplant. bp = 0.114 vs. pre-transplant. cp = 0.021 vs. pre-transplant. dp = 0.047 vs. pre-transplant. ep <0.05 vs. pre-transplant (related-samples Wilcoxon signed rank test). In line with our findings in the whole cirrhotic cohort [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar], we found that physical fatigue scores of PBC patients also improved but this failed to reach statistical significance (Table 1). In all, 5 out of 12 PBC patients (42%) had significant physical fatigue (physical fatigue scores >2 SD of controls) at pretransplant evaluation, which was also true in 3/10 (30%) of PBC patients and 37% of all cirrhotic patients [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] at 1 year post-transplant. Two out of 4 physically fatigued PBC patients pretransplant who survived 1 year following transplantation continued to be physically fatigued post-transplant (50%) compared to 46% in the whole cirrhotic cohort [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Out of 6 PBC patients without significant physical fatigue pre-transplant who survived 1 year following transplantation, 1 (17%) developed significant physical fatigue post-transplant, compared to 22% in the whole cirrhotic cohort [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Thus, persistent fatigue following liver transplantation does not appear to be characteristic of PBC and a certain proportion of PBC and non-PBC cirrhotic patients appear to develop physical fatigue post-transplant [1Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 2Kalaitzakis E. Josefsson A. Castedal M. Henfridsson P. Bengtsson M. Hugosson I. et al.Factors related to fatigue in patients with cirrhosis before and after liver transplantation.Clin Gastroenterol Hepatol. 2012; 10: 174-181Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 3Aadahl M. Hansen B.A. Kirkegaard P. Groenvold M. Fatigue and physical function after orthotopic liver transplantation.Liver Transpl. 2002; 8: 251-259Crossref PubMed Scopus (79) Google Scholar, 4van Ginneken B.T.J. van den Berg-Emons R.J.G. van der Windt A. Tilanus H.W. Metselaar H.J. Stam H.J. et al.Persistent fatigue in liver transplant recipients: a two-year follow-up study.Clin Transplant. 2010; 24: E10-E16Crossref PubMed Scopus (48) Google Scholar]. The latter suggests that unidentified transplantation-related factors may be of importance for post-transplant fatigue in general. It is unclear, in the cohort of Carbone and colleagues [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] whether any patients developed fatigue de novo after transplantation. In conclusion, taken together our findings and those of Carbone and colleagues [[1]Carbone M. Bufton S. Monaco A. Griffiths L. Jones D.E. Neuberger J.M. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.J Hepatol. 2013; 59: 490-494Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] indicate that fatigue remains a problem following liver transplantation in cirrhotic patients with PBC as well as in patients transplanted for other indications. Some patients appear to develop physical fatigue post-transplant while persistent fatigue following liver transplantation does not appear to be characteristic of PBC as it is also noted in patients with cirrhosis transplanted for other indications. Hepatic encephalopathy could be of importance for fatigue in these patients pre-transplant and it would be important to include assessment of encephalopathy by appropriate testing in future studies. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.