Fatigue in Cirrhosis: Is Transplant the Answer?
Fatigue is a complex symptom that encompasses a range of complaints including malaise, exhaustion, lethargy, and loss of motivation and social interest. Chronic fatigue is common in the general population, affecting up to 20%.1 Many chronic diseases are associated with fatigue including rheumatoid arthritis, systemic lupus erythematosus,2 and multiple sclerosis.3 Fatigue is often a major factor in the reduction of quality of life associated with chronic disease. Furthermore, the symptom of fatigue does not typically correlate with traditional markers of disease activity, severity, disability, or clinical disease subtype.4, 5 The exact frequency of fatigue in patients with chronic liver disease is variable; however it does constitute the most common complaint.6, 7, 8 Any physician who manages patients with chronic liver disease will acknowledge the presence of fatigue in this patient population. However, because of difficulties in measuring and treating fatigue, it is often minimized.
The study by Kalaitzakis and colleagues9 in this issue of Clinical Gastroenterology and Hepatology follows cirrhotic patients longitudinally pre- and post liver transplantation. As expected, fatigue was greater in patients with cirrhosis as compared with the general population. Additionally, the degree of fatigue was related to the severity of cirrhosis; specifically, patients with higher Child–Pugh classification scores had more severe fatigue.
When discussing fatigue, it is important to differentiate between central and peripheral fatigue.4, 5 Peripheral fatigue, classically manifested by neuromuscular dysfunction and muscle weakness, does not appear to be the main factor in patients with liver disease in the absence of decompensated cirrhosis or liver failure. In comparison, central fatigue is characterized by difficulty performing physical and mental activities: a lack of self-motivation.10 Central fatigue is often associated with an increased perceived effort for tasks.
The prevalence of fatigue varies depending on the specific form of liver disease. Fatigue is well characterized in chronic cholestatic liver diseases including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis.11 In fact, fatigue is present in 50% to 80% of patients with PBC and can often be the presenting symptom.12, 13, 14 Fatigue in PBC has been shown to be a poor prognostic factor, as patients with higher fatigue scores had reduced survival.13 The predominance of fatigue in hepatitic liver pathology is less clearly defined, with chronic hepatitis C,7, 15, 16 autoimmune hepatitis,17 and nonalcoholic fatty liver disease5 the most commonly reported. Additionally, the discussion of fatigue in patients with chronic liver disease must be placed in the context of a diagnosis with an uncertain prognosis and associated social stigma. This patient population also frequently has coexisting psychological issues, including depression and anxiety.18 The presence of hepatic encephalopathy compounds this further. Therefore, the clinical expression of fatigue encompasses complex interactions with biological, psychosocial, and behavioral processes.11 This is supported in the current study where fatigue was highest amongst cirrhotic patients that were unemployed or disabled; again showing the complexity of the clinical picture in this group of patients. Patients with the highest level of fatigue had the lowest described quality of life. Additionally, a significant proportion of patients in the study had anxiety or depression, which dramatically improved post liver transplant.
The pathophysiology of fatigue is complex. Animal models and clinical studies have documented that chronic liver inflammation is associated with changes in the central nervous system (CNS) that manifest as behavioral modifications.19 The inflamed liver communicates with the brain and results in altered brain function. Abnormal central neurotransmission gives rise to behavioral changes in the absence of pathologic CNS tissue damage.20, 21, 22 The neurotransmitters that have been implicated in central fatigue include coricotropin-releasing hormone (CRH),23 serotonin,24 and noradrenaline.25 In fact, pharmacologic targeting of serotonin has proven to be advantageous in managing fatigue in some patients with liver disease.26, 27 In addition to altered neurotransmission, the liver can communicate with the brain via neural, immune cell, or cytokine-driven routes. The liver is innervated by vagal nerve afferents that respond to immune mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin-6.28, 29 Activated vagal nerves project to different regions of the brain, potentially driving subsequent behavior changes. However, it is likely that this neural pathway plays only a minor role in mediating fatigue in the setting of chronic liver disease because post liver transplant patients (in which the liver is deinnervated) often report little change in their fatigue30; a finding also supported by this current study. Inflammatory mediators and cytokines within the circulation can also interact with their cognate receptors, expressed on the surface of cerebral endothelial cells, to activate their corresponding signaling pathways and subsequently stimulate cells within the brain parenchyma through the release of secondary messengers, including prostaglandins and nitric oxide.31, 32 The CNS is protected by a blood-brain barrier which is impermeable to large, hydrophilic cytokine molecules. However, the circumventricular organs are regions of the brain that lack an intact blood-brain barrier. The fenestrated capillaries allow the passage of inflammatory molecules that can then activate microglia, resident immune cells of the brain.33, 34 Finally, glial cells and neurons within the brain are capable of producing de novo cytokines that can mediate behavior effects, including fatigue.32, 35
The basal ganglia is comprised of 6 nuclei that project to the limbic system and frontal cortex. Fatigue has been linked to alterations in neural activity within the basal ganglia.10 Magnetic resonance imaging (MRI) studies in PBC patients have demonstrated increased signal intensity in the basal ganglia in patients with high fatigue levels.36 A recent study using MRI and voxel-based morphometry, which measures brain tissue density and concentration, found a decrease in brain density in certain areas in patients with cirrhosis.37 The brain areas found to have scores most indicative of decreased brain density were the frontal and parietal regions and putamen for gray matter, and the cingulate gyrus and temporal and frontal regions for white matter. Interestingly, many of these brain areas overlap structurally and/or functionally with the basal ganglia. Intriguingly, post liver transplant patients in this study also had areas of decreased brain density, even several months after transplantation. Cirrhosis had not recurred in these patients, suggesting that neurological injury may be persistent, or at least very slow to improve. The study by Kalaitzakis and colleagues9 is unique as it longitudinally documents fatigue in patients before and after liver transplantation. In concordance with the above-mentioned MRI study, Kalaitzakis et al9 found that fatigue improved post liver transplantation, but only in a minority of patients. The degree of fatigue was still significantly higher than the control population. No specific etiologies of posttransplant fatigue were identified in this study and further work is warranted in this area.
Fatigue in the advanced stages of chronic liver disease is challenging to study due to potential overlap with symptoms associated with hepatic encephalopathy (HE). HE ranges from subtle neuropsychiatric disturbances, only apparent by performing psychometric testing (minimal HE), to varying degrees of confusion, stupor, and coma.38 However, HE is not a requirement for the development of changes within the CNS in patients with chronic inflammatory liver disease. Traditionally, HE was attributed to the toxic effects of ammonia on astroglial cells,39 with hyperammonemia leading to the accumulation of glutamine within astrocytes, causing brain edema due to osmotic stress.40 However, recent attention has focused on the role of systemic inflammation in the development of HE, possibly acting synergistically with ammonia toxicity, including blood-brain cytokine transfer and receptor-mediated cytokine signal transduction.41, 42 These proinflammatory mechanisms are similar in many ways to the pathophysiology underlying behavioral changes and fatigue in the setting of liver inflammation and/or cirrhosis.
Fatigue is a complex and prevalent symptom in patients with chronic liver disease. Several pathophysiological mechanisms for explaining the development of fatigue have been generated; however, our understanding of fatigue in patients with liver disease is still incomplete. Moreover, the issue of fatigue in these patients is even more problematic given the recent findings that liver transplantation often does not completely alleviate this debilitating symptom. Future studies will be imperative to further examine factors predictive of fatigue in post liver transplant patients, and should help to inform us as to potential therapeutic interventions which could be instituted in order to improve fatigue in this clinical setting. Importantly, studies such as that reported by Kalaitzakis et al9 will help us to counsel patients more effectively with regards to expectations post liver transplantation; including that their fatigue potentially may not be significantly improved.
References
Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation
Evangelos Kalaitzakis, Axel Josefsson, Maria Castedal, Pia Henfridsson, Maria Bengtsson, Irene Hugosson, Bengt Andersson, Einar Björnsson et al.
Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 174-181.e1, February 2012
Abstract
Background & Aims We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients.
Methods
A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T3 and T4, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year.
Results
Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05).
Conclusions
Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.
Methods
A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T3 and T4, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year.
Results
Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05).
Conclusions
Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.
Discussion Only
In the current study, we observed high fatigue levels in patients with cirrhosis undergoing pretransplant evaluation. Fatigue was related to impaired HRQL and to being unemployed or having disability pension. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of fatigue in these patients, whereas anemia and impaired renal function are of further importance in physical fatigue. Physical fatigue also appears to be of concern at 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant. Our findings are in line with previously published data showing increased fatigue levels in patients with decompensated cirrhosis compared with those with compensated cirrhosis or liver transplant recipients.39 Fatigue has also been shown to be common in patients with chronic liver disease, but only a fraction of the patients included in these studies had cirrhosis.1, 2, 4, 5, 6 Our study is a systematic evaluation of fatigue in cirrhosis, simultaneously assessing potential associations with psychological distress, hormone abnormalities, and HRQL, as well as the effect of transplantation.
Hypothalamic-pituitary-adrenal dysfunction resulting in hypocortisolism can be accompanied by weakness and fatigue. Hypocortisolism has been reported in patients with chronic fatigue syndrome and fatigued patients with other chronic conditions.12, 13, 25 In cirrhosis, dysfunction of the hypothalamic-pituitary-adrenal axis resulting in hypocortisolism has been previously described,21, 40, 41 and it has been shown to contribute to increased mortality in cirrhotic patients with sepsis.40, 41 Our findings suggest that hypocortisolism might also contribute to fatigue and thus impaired HRQL in cirrhosis.
Psychological distress was found to be a major determinant of fatigue in cirrhosis. It was more closely related to fatigue domains than cirrhosis severity or peripheral factors, such as cirrhosis complications with an impact on patient survival, were. This is in accordance with studies in chronic (liver and nonliver) disease reporting that fatigue correlates strongly with anxiety and depression.1, 5, 6, 12, 13 In our cohort, 23% of patients had significant anxiety or depression as assessed by the HAD, and a dramatic improvement in both fatigue and psychological distress was seen after transplant. Previous studies have questioned the role of depression in the development of fatigue in cholestatic liver disease,3, 42 and antidepressants do not improve cancer-related fatigue.43 Our findings, however, indicate that patients with cirrhosis and significant anxiety or depression confirmed by a psychiatrist might benefit from specific treatment for these disorders, which could lead to improvement in fatigue and HRQL. However, this would need to be formally tested in interventional trials.
Anemia, present in 60% of patients in our cohort, was a predictor of pretransplant physical fatigue. Previous studies have shown that anemia is common in cirrhotic patients and that hemoglobin levels are inversely related to the hepatic venous pressure gradient.44 Interestingly, 35% of patients were found to be anemic after transplant, but this did not affect fatigue. Although anemia in cirrhosis is probably multifactorial, it is conceivable that rigorous measures to treat known anemia causes, especially those related to portal hypertension, could potentially improve fatigue and HRQL.
Fatigue scores were found to be more closely related to Child–Pugh scores compared with the Model for End-Stage Liver Disease (MELD) score. This is in line with previously published data on the closer relationship of the Child–Pugh score with HRQL indexes compared with the MELD score.45 Ascites and hepatic encephalopathy are known to be important factors influencing HRQL in patients with cirrhosis46 and were also found to be associated with fatigue levels in the current study. The fact that the Child–Pugh score but not the MELD score includes ascites and encephalopathy might explain, at least in part, the better correlation with fatigue.
Renal function is often impaired in cirrhosis.16, 18 Although fatigue is common in patients with renal failure and hemodialysis,47 the potential association of renal function impairment with fatigue in patients with cirrhosis has not been previously reported to our knowledge. Renal function has been tested as a potential determinant of HRQL in different cohorts of patients with cirrhosis, but no statistically significant results were obtained.8, 19 However, serum creatinine was used as a measure of renal function in these studies, whereas the GFR assessed by 51 Cr-EDTA clearance was used in the current study.
Although fatigue domain scores improved after transplant, 37% of transplant recipients were physically fatigued 1 year after transplant. Previous studies have shown that physical fatigue is a major problem after liver transplantation,7, 9, 10, 11 but our study specifically assessed fatigue in patients with cirrhosis before and after transplantation in a longitudinal fashion. A discussion about the expected benefit of transplantation on survival is part of the normal pretransplantation consent. Equally, with improving long-term transplantation results, being able to discuss the effect of transplantation on HRQL is central to an informed process. In the current study, almost half of fatigued patients before transplant remained fatigued at 1 year after transplant. However, no distinct potential cause of post-transplant fatigue could be identified. Further studies are clearly warranted on fatigue in transplant recipients.
The main strength of our study is its design, ie, it was a prospective longitudinal study in which validated HRQL instruments were used. Potential determinants of fatigue were carefully characterized, such as 51 Cr-EDTA clearance for GFR assessment, psychometric tests and serum ammonium ion measurements for hepatic encephalopathy, and anthropometry and DEXA measurements for nutritional status. One of the limitations of our study is potential selection bias because patients were recruited from a transplant program. Similarly, patients unable to fill in questionnaires were excluded, which might have underestimated the impact of more severe grades of hepatic encephalopathy on fatigue. Also, serum total cortisol measurements, used in the current study, are thought to overstate adrenal insufficiency in cirrhosis.21 However, hypoalbuminemia (<25 g/L) is the only reported risk factor for misdiagnosis of adrenal insufficiency by serum total cortisol assays.21 In the present study, only 1 patient with low serum cortisol had albumin <25 g/L, and exclusion of this patient from the analysis did not alter our results. Ideally, however, future studies investigating the role of glucocorticoids on fatigue in cirrhosis should use salivary cortisol measurements (not affected by hypoalbuminemia21) and synachten testing to identify patients with altered cortisol response.40, 41 Finally, controls were only asked to complete the FIS and not the questionnaire related to psychological distress (HAD), and they did not undergo any blood tests. In an attempt to improve the response rate of controls, published data on HAD results from the general Swedish population34 and established cutoff values of the laboratory of our institution38 were used.
In conclusion, patients with cirrhosis show increased fatigue, which impairs HRQL. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of most fatigue domains, whereas anemia and impaired renal function are of further importance in physical fatigue. Liver transplantation was associated with improvement in fatigue, but physical fatigue appeared to be of concern 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant.
Hypothalamic-pituitary-adrenal dysfunction resulting in hypocortisolism can be accompanied by weakness and fatigue. Hypocortisolism has been reported in patients with chronic fatigue syndrome and fatigued patients with other chronic conditions.12, 13, 25 In cirrhosis, dysfunction of the hypothalamic-pituitary-adrenal axis resulting in hypocortisolism has been previously described,21, 40, 41 and it has been shown to contribute to increased mortality in cirrhotic patients with sepsis.40, 41 Our findings suggest that hypocortisolism might also contribute to fatigue and thus impaired HRQL in cirrhosis.
Psychological distress was found to be a major determinant of fatigue in cirrhosis. It was more closely related to fatigue domains than cirrhosis severity or peripheral factors, such as cirrhosis complications with an impact on patient survival, were. This is in accordance with studies in chronic (liver and nonliver) disease reporting that fatigue correlates strongly with anxiety and depression.1, 5, 6, 12, 13 In our cohort, 23% of patients had significant anxiety or depression as assessed by the HAD, and a dramatic improvement in both fatigue and psychological distress was seen after transplant. Previous studies have questioned the role of depression in the development of fatigue in cholestatic liver disease,3, 42 and antidepressants do not improve cancer-related fatigue.43 Our findings, however, indicate that patients with cirrhosis and significant anxiety or depression confirmed by a psychiatrist might benefit from specific treatment for these disorders, which could lead to improvement in fatigue and HRQL. However, this would need to be formally tested in interventional trials.
Anemia, present in 60% of patients in our cohort, was a predictor of pretransplant physical fatigue. Previous studies have shown that anemia is common in cirrhotic patients and that hemoglobin levels are inversely related to the hepatic venous pressure gradient.44 Interestingly, 35% of patients were found to be anemic after transplant, but this did not affect fatigue. Although anemia in cirrhosis is probably multifactorial, it is conceivable that rigorous measures to treat known anemia causes, especially those related to portal hypertension, could potentially improve fatigue and HRQL.
Fatigue scores were found to be more closely related to Child–Pugh scores compared with the Model for End-Stage Liver Disease (MELD) score. This is in line with previously published data on the closer relationship of the Child–Pugh score with HRQL indexes compared with the MELD score.45 Ascites and hepatic encephalopathy are known to be important factors influencing HRQL in patients with cirrhosis46 and were also found to be associated with fatigue levels in the current study. The fact that the Child–Pugh score but not the MELD score includes ascites and encephalopathy might explain, at least in part, the better correlation with fatigue.
Renal function is often impaired in cirrhosis.16, 18 Although fatigue is common in patients with renal failure and hemodialysis,47 the potential association of renal function impairment with fatigue in patients with cirrhosis has not been previously reported to our knowledge. Renal function has been tested as a potential determinant of HRQL in different cohorts of patients with cirrhosis, but no statistically significant results were obtained.8, 19 However, serum creatinine was used as a measure of renal function in these studies, whereas the GFR assessed by 51 Cr-EDTA clearance was used in the current study.
Although fatigue domain scores improved after transplant, 37% of transplant recipients were physically fatigued 1 year after transplant. Previous studies have shown that physical fatigue is a major problem after liver transplantation,7, 9, 10, 11 but our study specifically assessed fatigue in patients with cirrhosis before and after transplantation in a longitudinal fashion. A discussion about the expected benefit of transplantation on survival is part of the normal pretransplantation consent. Equally, with improving long-term transplantation results, being able to discuss the effect of transplantation on HRQL is central to an informed process. In the current study, almost half of fatigued patients before transplant remained fatigued at 1 year after transplant. However, no distinct potential cause of post-transplant fatigue could be identified. Further studies are clearly warranted on fatigue in transplant recipients.
The main strength of our study is its design, ie, it was a prospective longitudinal study in which validated HRQL instruments were used. Potential determinants of fatigue were carefully characterized, such as 51 Cr-EDTA clearance for GFR assessment, psychometric tests and serum ammonium ion measurements for hepatic encephalopathy, and anthropometry and DEXA measurements for nutritional status. One of the limitations of our study is potential selection bias because patients were recruited from a transplant program. Similarly, patients unable to fill in questionnaires were excluded, which might have underestimated the impact of more severe grades of hepatic encephalopathy on fatigue. Also, serum total cortisol measurements, used in the current study, are thought to overstate adrenal insufficiency in cirrhosis.21 However, hypoalbuminemia (<25 g/L) is the only reported risk factor for misdiagnosis of adrenal insufficiency by serum total cortisol assays.21 In the present study, only 1 patient with low serum cortisol had albumin <25 g/L, and exclusion of this patient from the analysis did not alter our results. Ideally, however, future studies investigating the role of glucocorticoids on fatigue in cirrhosis should use salivary cortisol measurements (not affected by hypoalbuminemia21) and synachten testing to identify patients with altered cortisol response.40, 41 Finally, controls were only asked to complete the FIS and not the questionnaire related to psychological distress (HAD), and they did not undergo any blood tests. In an attempt to improve the response rate of controls, published data on HAD results from the general Swedish population34 and established cutoff values of the laboratory of our institution38 were used.
In conclusion, patients with cirrhosis show increased fatigue, which impairs HRQL. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of most fatigue domains, whereas anemia and impaired renal function are of further importance in physical fatigue. Liver transplantation was associated with improvement in fatigue, but physical fatigue appeared to be of concern 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant.
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