Determining the nature and impact of fatigue after liver transplantation

Abstract

For the past 20 years, a number of publications have described the success of liver transplantation (LT) in terms of patient and graft survival. In turn, a sizable body of literature has demonstrated that significant improvements in health-related quality of life (HRQL) result from LT when compared to preoperative states affected by end-stage liver disease.1, 2 In the majority of reports, however, the average HRQL for a group of LT recipients (both short- and long-term) is still reduced when compared to age- and sex-matched general population data.2, 3 While symptoms including pruritus and hepatic encephalopathy often contribute to poor HRQL and subsequently resolve with LT, a similar explanation for the symptom of fatigue is not as easily proposed. LT, liver transplantation; HRQL, health-related quality of life; FSS, fatigue severity score. Natural history and controlled trial investigations described the presence of fatigue in a majority of patients with various chronic liver diseases. Primary biliary cirrhosis4 and chronic hepatitis C5 have been the most common etiologies studied. Further investigation reveals that fatigue is often independent of hepatic disease severity6, 7 but usually intensifies with progressive liver failure. Alterations in central neurotransmission, impaired corticotrophin-releasing hormone response, and systemic cytokine release have been hypothesized yet remain unproven as putative mechanisms.8 Fatigue after LT has also been described in a number of investigations to date.9-11 The natural history of this symptom, however, remains uncertain. Among patients undergoing LT for cholestatic liver disease, the presence of significant fatigue was commonly observed among recipients for up to 1 year after LT.9 Similar findings were noted from a multicenter database report of 346 patients undergoing LT for various etiologies of chronic liver disease.10 Determining the frequency and severity of fatigue in this population, however, has not been performed to date. In this month's edition of Liver Transplantation, van den Berg-Emons and colleagues11 present a cross-sectional investigation examining the frequency and risk factors associated with fatigue after LT. A total of 96 recipients (45 men and 51 women) comprised the study cohort. The major hepatic disease etiologies for which LT was performed included viral (25%) and cholestatic (24%) etiologies. Only 6% of patients were transplanted for alcoholic liver disease. Exclusion criteria were noted for severe concomitant medical conditions (specific details unknown) or LT within 3 weeks of study enrollment. The nature and severity of fatigue was assessed using the Fatigue Severity Score (FSS) and Multidimensional Fatigue Inventory-20 instruments, which are known for excellent reliability and validity.6, 12 Level of perceived disability was characterized by the Sickness Impact Profile, which has been previously used in patients with liver disease undergoing transplantation.13 Finally, the Dutch version of the Short-Form 36 health survey was administered to assess the level of association between fatigue severity and health-related quality of life. In this study, the prevalence rate of fatigue was 66% (defined by FSS scores >1 standard deviation above the mean score in healthy individuals). An estimated 44% of LT recipients had severe involvement with fatigue (defined by an FSS score >2 standard deviations beyond the mean). In this cohort, the presence of reduced physical function and low activity level were strongly associated with self-reported fatigue. Risk factors including age, sex, self-experienced disability, and health-related quality of life were also found to influence the degree of fatigue in LT recipients. The strengths of this investigation include the following: (1) the use of validated instruments for quantifying fatigue severity, (2) confirmation of the role of physical function as a main determinant of fatigue after LT, and (3) description of the strong relationship between fatigue and impaired HRQL after LT. However, these findings conflict, in part, with results from Aadahl et al.14, where fatigue was less common in patients undergoing LT 4-5 years previously compared to patients receiving LT <3 years from study enrollment. In the current study, the duration of time since liver transplantation had no significant relationship with the occurrence of fatigue. Two potentially important reasons that may explain this difference relate to the methods used for assessing fatigue severity and the concept of response shift. The correlation between self-reported fatigue assessed by dichotomous response (yes/no) and quantitative measurement by validated instruments is highly variable. Personal experience is noted for similar degrees of variation in FSS scores among patients with primary biliary cirrhosis who admit or deny having any problems with fatigue in course of daily life (J.T., unpublished data). In turn, the correlation among multiple instruments (such as the FSS and Multidimensional Fatigue Inventory-20) for assessing similar degrees of fatigue severity may be poor.15 The concept of response shift is related to an individual's adaptation or positive reorientation in attitude based on surviving a traumatic or near-death experience.16 This could explain the low occurrence of fatigue in patients further away from LT when compared to individuals undergoing the procedure more recently. Important limitations in study methodology, however, should also be recognized when considering the nature of these results. The most important concerns relate to the absence of psychological assessment and the potential role for anxiety and depression to cause fatigue. Depression is common in patients with chronic liver disease and confounds the relationship between fatigue and health-related quality of life.17 Similar interactions can occur in LT recipients yet data on the frequency of psychiatric disturbance after LT are scant. The prevalence rate for anxiety and depression in the Aadahl study were <8%, suggesting that few patients would have described fatigue as a symptom of mental illness. However, this rate may vary tremendously by center and geographic location and thus require further study when assessing the burden of fatigue. Similar comments can be made about the influence of sleep disorders and obesity on fatigue, which were also not studied in this population as well. The potential impact of persistent hepatitis C viremia and/or recurrent disease on fatigue was also not addressed despite knowledge regarding the association between recurrent hepatitis C and HRQL.18 The current study describes an association between fatigue and reduced physical activity. Individuals reporting low levels of physical activity are more likely to have impaired pretransplant HRQL, be unemployed, have elevated body mass indices, and have problems related to osteoporosis and arthritis. In contrast, a relationship between increased physical activity and improved HRQL following LT has been observed.19 Recently, 2 investigations have also studied the potential effects of a physical rehabilitation program on improving fatigue and HRQL after LT. For patients attending a 2- to 6-month supervised exercise program within the first year after LT,20 a significant increase in physical function measured by maximal oxygen uptake and performance in the 6-minute walk was observed compared to preoperative levels. In turn, 100% of participants reported good to excellent levels of overall health and physical function after the intervention. The longitudinal benefits of structured exercise were also demonstrated21 with significant improvements in maximal oxygen uptake max, muscle strength, and HRQL occurring between 2 to 24 months after LT. In this study, the gains were most appreciable within the first 6 months. All performance measures, however, remained lower than values expected for the general population. By using quantitative methods and validated instruments, it appears that fatigue is a common and significant problem for selected LT recipients. Fatigue is also an important contributor to impaired HRQL after LT driven mainly by decrements in physical function based on investigations to date. As described previously,22 the time has come to shift gears by identifying efficacious interventions that improve physical function, fatigue, and HRQL in this population. This would best be done in the setting of randomized controlled trials. For patients whose fatigue is prominent yet remains unexplained or unresponsive to directed intervention such as exercise, the study of novel pharmacological therapies in clinical trials is also desired. Recent observations of impaired cognitive function after LT23 should also be examined in future studies as a potential cause of fatigue in patients with intact physical function.