Fatigue is considered to be common in chronic liver disease.

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: 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, and EINAR BJÖRNSSON* *Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg; Transplantation Institute, Sahlgrenska University Hospital, Gothenburg; and Department of Immunology, Sahlgrenska University Hospital, Gothenburg, Sweden See editorial on page 103. 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. METH- ODS: 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 T 3 and T 4, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor- 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). CON- CLUSIONS: 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. Keywords: Liver Disease; Tiredness; Exhaustion; Stress; Surgery. Fatigue is considered to be common in chronic liver disease. Although there are reports on fatigue in patients with cholestatic liver disease, 1 3 chronic hepatitis C, 4,5 and nonalcoholic fatty liver disease, 6 few of the patients in these studies had overt cirrhosis. Thus, published data on fatigue and its possible association with health-related quality of life (HRQL) in cirrhosis are scarce. Furthermore, fatigue is a troublesome and persistent symptom after liver transplantation However, to our knowledge, there are no longitudinal studies specifically addressing the effect of transplantation on fatigue in cirrhosis. The pathogenesis of fatigue in chronic diseases is usually multifactorial. 12,13 Patients with cirrhosis often experience psychological distress 14,15 and potentially debilitating complications such as hepatic encephalopathy, malnutrition, or hepatocellular carcinoma (HCC) that could lead to cognitive and physical weakness. However, it is unknown the extent to which these factors contribute to fatigue in cirrhosis. Hormonal abnormalities and systemic inflammation are common in cirrhosis. In particular, diabetes, 17 thyroid dysfunction, 20 dysfunction of the hypothalamic-pituitary-adrenal axis, 21 reduced dehydroepiandrosterone sulfate (DHEA-S), 22 and reduced serum testosterone 23 as well as increased interleukin-6 (IL-6) and tumor necrosis factor- (TNF- ) 24 have been reported. These abnormalities are thought to be involved in the pathogenesis of fatigue in noncirrhotic patients, 12,13,25 28 but it is unclear whether they contribute to fatigue in cirrhosis. Our primary aim was to evaluate the severity of fatigue in patients with cirrhosis undergoing assessment for transplantation in comparison with the general population. We also aimed to identify determinants of fatigue in these patients and to study its potential relation to HRQL as well as to assess the effect of liver transplantation on fatigue. Methods Patients A total of 108 consecutive patients with cirrhosis admitted in our institution for pretransplantation evaluation between May 2004 and April 2007 were prospectively enrolled. Inclusion criterion was cirrhosis of any cause. The diagnosis of cirrhosis was established histologically or based on the presence of at least 2 of the following: characteristic imaging features, varices, ascites, or increased international normalized ratio that could not be attributed to any other cause. Patients unable to understand Swedish as well as those unable to complete ques- Abbreviations used in this paper: BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; DHEA-S, dehydroepiandrosterone sulfate; EDTA, ethylenediaminetetraacetic acid; E2, estradiol; FIS, fatigue impact scale; GFR, glomerular filtration rate; HAD, hospital anxiety and depression; HCC, hepatocellular carcinoma; HOMA, homeostasis model assessment index; HRQL, health-related quality of life; IL-6, interleukin-6; MELD, Model for End-Stage Liver Disease; SD, standard deviation; SF-36, short-form 36; TNF-, tumor necrosis factor ; TSH, thyroid-stimulating hormone by the AGA Institute /$36.00 doi: /j.cgh

2 February 2012 FATIGUE IN LIVER CIRRHOSIS 175 tionnaires owing to severe cirrhosis complications or comorbidities were excluded. Patient data, such as cirrhosis etiology, previous variceal bleeding, HCC, and comorbid illness, were collected from medical records. The glomerular filtration rate (GFR) was measured by means of 51 Cr-ethylenediaminetetraacetic acid (EDTA) clearance. Ascites was assessed by transabdominal ultrasound. The study was approved by the ethics committee of Västra Götalandsregionen, and written informed consent was obtained from all patients. Assessment of Hepatic Encephalopathy Encephalopathy was graded clinically from 0 4 (West Haven criteria) and by means of the number connection tests A and B. 29 Fasting plasma ammonium ion levels were measured (CV% 2.1%; Roche Diagnostics, Scandinavia AB, Stockholm, Sweden). Hepatic encephalopathy was defined as overt according to West Haven criteria or as minimal if there was absence of overt encephalopathy and number connection test A and/or B score 3 standard deviations (SDs) of the general population. 29,30 Assessment of Nutritional Status Nutritional status was assessed by an experienced dietitian as previously described. 17 Body mass index (BMI) was calculated, and unintentional weight change ( 1 kg) during the previous 3 6 months was noted. Body fat and lean mass was also determined by dual-energy x-ray absorptiometry (DEXA). Malnutrition was defined as triceps skin-fold thickness and/or mid-arm muscle circumference 5th percentile, according to standard tables for the Swedish population, and/or BMI 20 kg/m 2 and/or weight loss 5% 10% in the previous 3 6 months. 31 Questionnaires The questionnaire booklet contained questions on work, marital status, and education as well as the following questionnaires. Fatigue impact scale. This questionnaire was used to assess perceived fatigue during the last month on 3 subscales: physical (10 items), cognitive (10 items), and psychosocial functioning (20 items). Each item uses a 5-grade scale (0 4), yielding a maximum of 160. Higher scores indicate increased fatigue. 32 The fatigue impact scale (FIS) has been used in chronic liver disease. 1 3,5,6 To provide a control group, the FIS was mailed to a random sample (n 2000) from the general population in Gothenburg. A total of 858 subjects (49% female) completed the questionnaire. From this group of subjects, 2 age- and gender-matched controls were provided for each patient with cirrhosis (n 216). Patients were classified as fatigued if they had a FIS score 2 SDs compared with the general population cohort. Hospital anxiety and depression scale. The hospital anxiety and depression scale (HAD) was used to assess psychological distress. Each item uses a 4-grade scale (0 3) with subscales for anxiety (7 items) and depression (7 items). Higher scores indicate higher levels of anxiety and depression. 33 There are published normative data from the Swedish population. 34 Short-form 36. Short-form 36 (SF-36) was used to assess HRQL (physical, emotional, and social functioning). 35,36 It consists of 8 domains, scored from Higher scores indicate better HRQL. Measurement of Hormones and Cytokines Fasting serum insulin was determined in all patients at about 7:00 8:00 AM on the day after enrollment in the study (CV 5.9%; Roche Diagnostics, Scandinavia). Fasting plasma glucose was measured on the same occasion. Patients were considered to have diabetes if they were receiving antidiabetic treatment or had fasting plasma glucose 7 mmol/l. Insulin resistance was expressed as the homeostasis model assessment index (HOMA-IR). 37 In a subset of patients (n 80/108, 74%), additional blood samples were drawn on the same occasion. Plasma was immediately separated by centrifugation at 1000g (4 C) and stored at 80 C until subsequent analysis for thyroid-stimulating hormone (TSH) (CV 7%; Roche Diagnostics, Germany, Mannheim, Germany), free T 4 and T 3 (CV 10%; Roche Diagnostics, Germany), cortisol (CV 11%; Roche Diagnostics, Germany), DHEA-S (CV 12%; Diagnostic Products Corporation, Los Angeles, CA), estradiol (E 2 ) (CV 11%; DiaSorin s.r.l., Vercelli, Italy), and free testosterone (CV 10%; Diagnostic Products Corporation). The limits of normal of our institution for each of these hormones were used to identify patients with hormonal abnormalities. 38 IL-6 and TNF- were also measured (Siemens Medical Solutions Diagnostics, Tarrytown, NY). Serum IL-6 5 pg/ml and TNF- 20 pg/ml were considered normal on the basis of analysis from 50 healthy blood donors. Follow-up One Year After Transplantation Transplant recipients were followed up 1 year after transplantation and were asked to complete the same questionnaires. Patient data, such as rejection and immunosuppression, were collected from medical records. Statistics Data are expressed as mean (SD) or n (%) as appropriate. Analysis of variance or the Mann Whitney test was performed to compare continuous variables. The Pearson or Spearman coefficient was calculated for correlation analysis. The 2 or Fisher exact test was used for comparisons between categorical variables as appropriate. The Wilcoxon test was used to assess changes in fatigue after transplantation. In an attempt to identify independent predictors of fatigue at baseline, all parameters univariately related to FIS domain and total scores were entered into multiple stepwise linear regression analyses. To avoid inflated type 1 error because of multiple tests, only variables univariately related at.005 with fatigue scores were entered into regression analyses. We modeled the relationship between fatigue and patient features by using a staged approach. The first stage included clinical variables (available in all patients), whereas the second stage added hormone data (available in 74% of patients). All tests were two-tailed and conducted at a 5% significance level. Results Baseline characteristics of all patients (n 108) are shown in Table 1. Patients with cirrhosis showed increased fatigue levels (Figure 1). The statistical power of all fatigue comparisons between controls and patients with cirrhosis before transplantation was 88%. All FIS domain scores were related to all SF-36 domains (r 0.44 to 0.77, P.001). Patients working or studying had significantly lower fatigue levels (physical and cognitive domains) compared with those who were unemployed or on disability pension (P.05 for both).

3 176 KALAITZAKIS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2 Table 1. Baseline Characteristics of All Patients With Cirrhosis at Pretransplantion Evaluation (n 108) Age (y) 52 (10) Gender (F/M) 36/72 (33%/67%) Etiology of liver cirrhosis ALD or mixed 39 (37%) Viral 25 (23%) Cholestatic 22 (20%) Cryptogenic/nonalcoholic 9 (8%) steatohepatitis Other 13 (12%) Ascites (ever) 67 (62%) Previous ascites 64 (59%) Ascites at pretransplant 35 (32%) evaluation Hepatic encephalopathy Overt 22 (20%) Minimal 9 (8%) Esophageal/gastric varices 77 (71%) Previous variceal bleed 32 (30%) HCC a 19 (18%) Severity of liver cirrhosis Child Pugh class 16/55/37 (15%/51%/34%) Child Pugh score 9 (2.3) MELD score 15 (5.8) Malnutrition 28 (26%) Diabetes mellitus 31 (29%) HOMA-IR 9.9 (13.3) Anemia b 64 (59%) GFR (ml min m 2 ) 85 (28) C-reactive protein (mg L 1 ) 11 (20) Comorbid illness c 76 (70%) Living with a spouse/partner 68 (63%) Years of school education 10 y 54 (50%) Working/studying 44 (41%) Anxiety according to HAD 69/22/17 (64%/20%/16%) (none/borderline/significant) Depression according to HAD 68/25/15 (63%/23%/14%) (none/borderline/significant) NOTE. Data are presented as mean (SD) or n (%) as appropriate. ALD, alcoholic liver disease. a Mean size of HCC was 6.0 cm (SD, 3.0 cm); median, 5.3 cm; range, 3 13 cm. b Anemia was defined as blood hemoglobin 117 g/l in women or 134 g/l in men. c Patients who had other types of disease apart from liver cirrhosis. Apart from patients with diabetes mellitus, 19% had gastrointestinal, 14% had cardiovascular, 11% had psychiatric, 8% had respiratory, 6% had rheumatological, and 13% other comorbid illness. patients with borderline or significant anxiety (12% vs 21% and 8% vs 16%, respectively; P.034) and borderline or significant depression (9% vs 23% and 6% vs 14%, respectively; P.001), as assessed by the HAD. Both anxiety and depression were related to fatigue (Table 2). Fatigue at Baseline in Relation to Hormonal and Cytokine Levels Two patients had known hypothyroidism (treated with thyroxine). None had any other known endocrine disease (except diabetes). A total of 80 patients (74%) consented to having blood samples drawn for hormonal and cytokine analyses. Patients who consented, when compared with those who did not consent to this part of the study, did not differ significantly in etiology or severity of liver cirrhosis or in total or domain scores of FIS, HAD, or SF-36 (data not shown). Five patients had increased TSH but were euthyroid (normal T 4 ). Two of 80 patients (2.5%) had T 4 levels and 27 of 80 (34%) had T 3 levels under the lower limit of normal. Cortisol, DHEA-S, free testosterone, and E 2 were under the lower limit of normal in 13 of 80 (16%), 61 of 80 (76%), 16 of 80 (15%), and 22 of 80 (28%), respectively. Also, 63 of 80 (79%) had increased IL-6, and 16 of 80 (20%) had increased TNF-. Having low T 3, cortisol, or testosterone levels was significantly related to increased fatigue levels (Table 3). Patients with significant depression did not have low serum cortisol levels more often than patients without significant depression according to the HAD (data not shown). Serum total cortisol assays are known to overstate adrenal insufficiency in the setting of hypoalbuminemia ( 25 g/l). 21 In our cohort only 1 patient with low serum cortisol had hypoalbuminemia, and exclusion of this patient from the analysis did not alter the relation of cortisol with fatigue (data not shown). Regression Analyses In linear regression analysis, anxiety and depression as well as cirrhosis severity and low cortisol were found to be major determinants of fatigue at baseline (Table 4). Anemia and impaired renal function were also independent predictors of physical fatigue (Table 4). Effect of Liver Transplantation on Fatigue Sixty-six of 108 patients (61%) underwent transplantation. Four patients died before follow-up at 1 year after trans- Clinical Predictors of Fatigue at Baseline Cirrhosis severity, ascites, and hepatic encephalopathy were related to fatigue (Table 2). Plasma ammonium ion levels were related to physical, cognitive, and total (r , P.05) but not to psychosocial FIS scores (P.05). Neither indexes of malnutrition nor fat or lean mass as measured by DEXA were related to fatigue (P.05 for all). Marital or educational status did not affect fatigue levels (P.05). Psychological Distress and Fatigue at Baseline Before HAD testing, 11 patients had been diagnosed with depression, and 1 had been diagnosed with anxiety disorder. Compared with the general population, 34 there were more Figure 1. Severity of fatigue assessed as FIS domain and total scores in patients with liver cirrhosis before (n 108, black bars) and after (n 60, gray bars) liver transplantation in comparison with controls (n 216, white bars). *P.005. **P.001.

4 Table 2. Factors Univariately Related to Fatigue Levels of Patients With Cirrhosis at Pretransplant Evaluation (n 108) Physical FIS domain Psychosocial FIS domain Cognitive FIS domain Total FIS score Age 52 y a 22 (10) vs 18 (12) 33 (21) vs 31 (21) 15 (12) vs 15 (11) 71 (40) vs 63 (42) Gender (F vs M) 21 (12) vs 20 (11) 37 (23) vs 29 (19) 18 (12) vs 13 (11) 76 (45) vs 63 (38) Etiology of liver cirrhosis ALD or mixed 22 (11) vs 19 (11) 33 (22) vs 32 (20) 15 (13) vs 15 (11) 70 (44) vs 66 (39) Viral 19 (12) vs 21 (11) 30 (20) vs 33 (21) 14 (11) vs 15 (11) 62 (41) vs 69 (41) Cholestatic 20 (9) vs 20 (12) 33 (17) vs 32 (22) 16 (8) vs 15 (12) 69 (31) vs 67 (43) Ascites (ever) 24 (10) vs 14 (10) b 38 (21) vs 22 (16) b 17 (12) vs 11 (10) c 49 (40) vs 47 (33) b Hepatic encephalopathy (none vs minimal vs overt) 18 (11) vs 22 (5) vs 27 (8) c 29 (21) vs 32 (14) vs 46 (16) c 13 (11) vs 15 (8) vs 24 (9) b 61 (42) vs 68 (24) vs 98 (30) c Esophageal or gastric varices 21 (11) vs 16 (12) 34 (20) vs 26 (21) 16 (11) vs 12 (11) 71 (40) vs 54 (42) Previous variceal bleed 20 (12) vs 20 (12) 30 (20) vs 33 (21) 15 (11) vs 15 (11) 65 (40) vs 68 (42) HCC d 15 (12) vs 21 (11) 22 (19) vs 34 (20) 11 (9) vs 16 (12) 49 (38) vs 71 (41) Severity of liver cirrhosis Child Pugh class (A/B/C) 13 (11) vs 18 (11) vs 26 (9) b 21 (17) vs 28 (19) vs 42 (19) b 8 (8) vs 13 (11) vs 20 (11) c 43 (35) vs 60 (38) vs 88 (38) b Child Pugh score r 0.39 b r 0.37 b r 0.37 b r 0.40 b MELD score r 0.30 c r 0.30 c r 0.27 c r 0.30 c Malnutrition 22 (10) vs 19 (11) 35 (21) vs 30 (21) 16 (12) vs 14 (11) 73 (42) vs 63 (41) Diabetes mellitus 20 (11) vs 20 (11) 30 (20) vs 33 (21) 13 (10) vs 16 (12) 64 (38) vs 68 (42) HOMA-IR r 0.09 r 0.05 r 0.01 r 0.05 Anemia 23 (10) vs 16 (12) c 35 (19) vs 27 (22) 16 (11) vs 13 (11) 75 (39) vs 56 (43) GFR 85 e (ml min m 2 ) 24 (10) vs 16 (11) c 35 (20) vs 28 (20) 16 (12) vs 13 (10) 75 (40) vs 57 (40) C-reactive protein r 0.14 r 0.13 r 0.11 r 0.13 Comorbid illness f 21 (10) vs 19 (13) 33 (20) vs 30 (23) 15 (10) vs 15 (13) 68 (38) vs 64 (47) Anxiety according to HAD (none/borderline/significant) 17 (11) vs 23 (9) vs 29 (9) b 25 (18) vs 37 (17) vs 55 (14) b 11 (10) vs 17 (8) vs 27 (8) b 54 (37) vs 77 (30) vs 112 (29) b Depression according to HAD (none/borderline/significant) 17 (11) vs 24 (8) vs 29 (9) b 25 (19) vs 40 (14) vs 53 (17) b 11 (10) vs 17 (8) vs 28 (10) b 53 (38) vs 81 (27) vs 111 (33) b NOTE. Data presented as mean (SD) of FIS scores in the patient group indicated in the first column compared with the rest of the cohort. In the cases of Child Pugh score, MELD score, HOMA-IR, and C-reactive protein, the Pearson correlation coefficient (r) is presented. ALD, alcoholic liver disease. a Mean age in cohort was 52 years. b P.001. c P.005. d No significant correlation could be found between HCC size and total or domain FIS scores (P.05). e Mean GFR in the cohort was 85 ml min m 2. f Gastrointestinal, cardiovascular, psychiatric, respiratory, or rheumatological comorbid illness was not found to be related to total or domain FIS scores when tested separately (P.05 for all). February 2012 FATIGUE IN LIVER CIRRHOSIS 177

5 178 KALAITZAKIS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2 Table 3. Fatigue Levels in Patients With Cirrhosis and Hormonal and Cytokine Abnormalities as Compared With the Rest of the Cohort at Pretransplant Evaluation (n 80) Physical FIS domain Psychosocial FIS domain Cognitive FIS domain Total FIS score Low serum T 3 25 (8) vs 18 (12) a 42 (18) vs 28 (22) a 19 (10) vs 13 (11) a 86 (35) vs 60 (43) a Low serum cortisol 29 (7) vs 19 (12) a 50 (17) vs 29 (21) a 24 (9) vs 13 (11) a 103 (31) vs 62 (41) b Low serum DHEA-S 22 (11) vs 18 (11) 34 (22) vs 30 (20) 15 (11) vs 15 (11) 70 (43) vs 62 (41) Low serum testosterone 28 (6) vs 19 (12) a 42 (17) vs 30 (22) 17 (10) vs 15 (11) 87 (32) vs 64 (43) Low serum E 2 24 (9) vs 19 (12) 38 (19) vs 31 (22) 17 (10) vs 14 (11) 79 (38) vs 64 (44) Increased serum IL-6 22 (11) vs 15 (12) 35 (21) vs 24 (20) 15 (11) vs 13 (12) 72 (41) vs 52 (44) Increased serum TNF- 22 (12) vs 20 (11) 39 (24) vs 31 (21) 19 (11) vs 14 (11) 80 (46) vs 65 (41) NOTE. Data presented as mean (SD) of FIS scores in the patient group indicated in the first column compared with the rest of the cohort. a P.005. b P.001. plantation, and 2 were lost to follow-up. Thus, follow-up data were available in 60 patients (Supplementary Table 1). FIS domain and total scores had improved 1 year after transplantation, but transplant recipients still had higher physical fatigue compared with controls (Figure 1). Thirty-seven of 60 patients (62%) had a pretransplant physical FIS score 2 SDs of controls and thus were classified as physically fatigued. Seventeen of 37 physically fatigued patients (46%) before transplant continued to be physically fatigued after transplant (P.004). After transplant, 22 of 60 (37%) were classified as physically fatigued. Clinical Predictors of Remaining Physically Fatigued After Transplant Patients remaining physically fatigued (n 17/37), compared with those whose fatigue levels dropped 2 SDs of the general population (n 20/37) after transplant, had higher physical, psychosocial, and total FIS domain scores at baseline (30 [6] vs 25 [5] P.022, 50 [13] vs 36 [15] P.008, and 103 [26] vs 79 [29] P.015, respectively) and had more frequent significant or borderline depression at baseline as assessed by the HAD (35% vs 15% and 41% vs 15%, respectively, P.019). However, the 2 groups did not differ in any other baseline or transplant-related factor (data not shown, P.05). At 1 year after transplant, the proportions of patients with depression or anxiety as assessed by HAD did not differ significantly from the general population (data not shown). Discussion 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 Table 4. Independent Predictors of Fatigue Severity at Pretransplant Evaluation in Multiple Linear Regression Analyses Stage 1 (all patients, n 108) Stage 2 (hormone data, n 80) Unstandardized beta coefficient P value Unstandardized beta coefficient P value Physical FIS domain HAD depression (none/borderline/significant) HAD anxiety (none/borderline/significant) GFR Previous or current ascites Anemia Low cortisol Psychosocial FIS domain HAD depression (none/borderline/significant) HAD anxiety (none/borderline/significant) Child Pugh score Low cortisol Cognitive FIS domain HAD depression (none/borderline/significant) HAD anxiety (none/borderline/significant) Child Pugh score Low cortisol Total FIS score HAD depression (none/borderline/significant) HAD anxiety (none/borderline/significant) Child Pugh score Low cortisol

6 February 2012 FATIGUE IN LIVER CIRRHOSIS 179 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 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 hypothalamicpituitary-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 cirrhosis 46 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 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 hypoalbuminemia 21 ) 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 population 34 and established cutoff values of the laboratory of our institution 38 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.

7 180 KALAITZAKIS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2 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. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: /j.cgh References 1. Huet PM, Deslauriers J, Tran A, et al. Impact of fatigue on the quality of life of patients with primary biliary cirrhosis. Am J Gastroenterol 2000;95: Goldblatt J, Taylor PJ, Lipman T, et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002;122: Björnsson E, Simren M, Olsson R, et al. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol 2004;39: Barkhuizen A, Rosen HR, Wolf S, et al. 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8 February 2012 FATIGUE IN LIVER CIRRHOSIS 181 from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28: Analyslistan. Gothenburg, Sweden: Sahlgrenska University Hospital, Available at: Laboratoriemedicincom/Laboratoriemedicins-verksamheter/Klinisk- Kemi/Analyslistan/. Accessed December 9, van der Plas SM, Hansen BE, de Boer JB, et al. Generic and disease-specific health related quality of life in non-cirrhotic, cirrhotic and transplanted liver patients: a cross-sectional study. BMC Gastroenterol 2003;3: Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology 2006;43: Fernández J, Escorsell A, Zabalza M, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival. Hepatology 2006;44: van Os E, van den Broek WW, Mulder PG, et al. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007;46: Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010:CD Qamar AA, Grace ND, Groszmann RJ, et al. Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis. Clin Gastroenterol Hepatol 2009;7: Kanwal F, Hays RD, Kilbourne AM, et al. Are physician-derived disease severity indices associated with health-related quality of life in patients with end-stage liver disease? Am J Gastroenterol 2004;99: Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120: Jhamb M, Argyropoulos C, Steel JL, et al. Correlates and outcomes of fatigue among incident dialysis patients. Clin J Am Soc Nephrol 2009;4: Reprint requests Address requests for reprints to: Evangelos Kalaitzakis, MD, PhD, Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Magtarmlab, Vita stråket 12, Sahlgrenska University Hospital, Gothenburg, Sweden. kalvag@hotmail.com; fax: (46) Conflicts of interest The authors disclose no conflicts.

9 February 2012 FATIGUE IN LIVER CIRRHOSIS 181.e1 Supplementary Table 1. Transplant-Related Data of Patients Followed up at 1 Year After Transplant (n 60) Age at follow-up (y) 52 (10) Gender (F/M) 20/40 (33%/67%) Etiology ALD or mixed 21 (35%) Viral 13 (22%) Cholestatic 17 (28%) Other 9 (15%) HCC 12 (20%) Retransplantation 5 (8%) Rejection 27 (45%) Anti-thymocyte globulin/okt3 treatment 13 (22%) Immunosuppression (except steroids) Tacrolimus alone 50 (83%) Tacrolimus mucophenolate 8 (13%) Other 2 (4%) Renal function Dialysis 5 (8%) GFR (ml min m 2 ) 58 (25) Anemia 21 (35%) Living with a spouse/partner 37 (62%) Years of school education 10 y 33 (55%) Working/studying 25 (42%) NOTE. Data are presented as mean (SD) or n (%) as appropriate. ALD, alcoholic liver disease.