February 15, 2012

Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation

From Clinical Gastroenterology and Hepatology

Evangelos Kalaitzakis; Axel Josefsson; Maria Castedal; Pia Henfridsson; Maria Bengtsson; Irene Hugosson; Bengt Andersson; Einar Björnsson

Posted: 02/10/2012; Clin Gastroenterol Hepatol. 2012;10(2):174-181. © 2012 AGA Institute

Abstract and Introduction
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.

Introduction

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.[7–11] 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)[16–19] 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-α (TNF-α)[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 questionnaires 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/m2 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 0–100. 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 T4 and T3 (CV 10%; Roche Diagnostics, Germany), cortisol (CV 11%; Roche Diagnostics, Germany), DHEA-S (CV 12%; Diagnostic Products Corporation, Los Angeles, CA), estradiol (E2) (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-α were also measured (Siemens Medical Solutions Diagnostics, Tarrytown, NY). Serum IL-6 <5 pg/mL and TNF-α <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 χ2 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).

757995-fig1

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.

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 = 0.19–0.28, 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 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 T4). Two of 80 patients (2.5%) had T4 levels and 27 of 80 (34%) had T3 levels under the lower limit of normal. Cortisol, DHEA-S, free testosterone, and E2 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-α. Having low T3, 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 transplantation, 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 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 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 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. 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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