Reply to: “Fatigue and liver transplantation in patients with primary biliary cirrhosis”
Authors: Marco Carbone, Sally Bufton, David E. Jones, James M. Neuberger
Journal: Journal of Hepatology (2014)

Fatigue and liver transplantation in patients with primary biliary cirrhosisJournal of HepatologyVol. 60Issue 6PreviewWe read with great interest the paper of Carbone et al. [1] 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]. Full-Text PDF Open AccessThe 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 We would like to thank Kalaitzakis et al. [[1]Kalaitzakis E. Bjornsson E. Fatigue and liver transplantation in patients with primary primary biliary cirrhosis.J Hepatol. 2014; 60: 1326-1328Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] for the comments on our article on the effect of liver transplantation (LT) on fatigue in patients with primary biliary cirrhosis (PBC) [[2]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 (61) Google Scholar]. 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. Kalaitzakis et al. [[1]Kalaitzakis E. Bjornsson E. Fatigue and liver transplantation in patients with primary primary biliary cirrhosis.J Hepatol. 2014; 60: 1326-1328Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] showed that fatigue improved after LT although fatigue scores remained higher than in controls from the general population. Of note, they found that the median fatigue impact score (FIS) after LT was 40, which is identical to the median FIS in a non-transplant PBC cohort, reported by Goldblatt et al. [[3]Goldblatt J. Taylor P.J. Lipman T. Prince M.I. Baragiotta A. Bassendine M.F. et al.The true impact of fatigue in primary biliary cirrhosis: a population study.Gastroenterology. 2002; 122: 1235-1241Abstract Full Text Full Text PDF PubMed Google Scholar]. In our study [[2]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 (61) Google Scholar] fatigue score, assessed using the PBC-40, was 26 ± 10 at two years after LT, which was lower compared to a 'non transplant' PBC control cohort (31 ± 12; p = 0.03); however, the fatigue score was higher than a 'normal' age- and sex-matched control group (18 ± 6; p <0.0001). The work of Kalaitzakis et al., along with our data, casts some light on the pathophysiology of fatigue, as they suggest the abnormalities that result in fatigue are either irreversible or that they do not arise in the affected liver. These findings also are helpful in identifying the role of transplantation in symptomatic patients with PBC. Chronic fatigue is a feature of HE and the relationship between fatigue and HE in patients with PBC and other chronic liver conditions is complex and not fully understood. Emerging data suggest that continued cognitive impairment post-transplant is seen in particularly in patients with recurrent encephalopathy pre-transplant. This suggests that the neuropsychiatric abnormalities of encephalopathy, as the fatigue of PBC, do not fully revert post-transplant [[4]Sotil E.U. Gottstein J. Ayala E. Randolph C. Blei A.T. Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver trans-plantation.Liver Transpl. 2009; 15: 184-192Crossref PubMed Scopus (114) Google Scholar]. Larger, longitudinal studies are required to address this issue. In the Birmingham liver unit, HE is routinely assessed using the Number Connection Test and graded clinically from 0–4 (West Haven criteria). In our study no patient was excluded because of overt HE. In the final cohort analyzed, only two had clinically evident HE who had grade 2 HE before LT. In one patient the fatigue persisted after transplant with the same severity (PBC-40 score of 45 and 46, before and two-years after LT). In the other, the fatigue improved but remained of moderate severity (falling from 46 before transplant to 30 two-years after LT). Therefore we do not believe the high fatigue scores before LT were suggestive of HE-related fatigue. Furthermore, we did not find any correlation between the severity of the liver disease and the severity of the fatigue, in keeping with previous literature. Minimal HE can only be determined by a comprehensive neurological assessment of consciousness, cognitive, and motor function and this has not been part of our routine pre-transplant assessment. Kalaitzakis et al. have shown the persistence of fatigue after LT in those with other indications. However, data from more than half of the patients was excluded from the final analysis. As suggested by Kalaitzakis et al. unidentified transplantation-related factors may be relevant for post-transplant fatigue. However, as shown in Fig. 3 of our paper [[2]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 (61) Google Scholar], no patient developed fatigue de novo after transplantation. Further studies are needed to establish if the changes seen here are unique to PBC and to identify the mechanisms responsible for this symptom, and so develop appropriate treatments. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.